The Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167

THE ALKALOIDS
Chemistry and Physiology
VOLUME XVI
This Page Intentionally Left Blank
THE ALIMLOIDS
Chemistry and Physiology
Edited by
R. H. F. MANSKE
Department of Chemistry, University of Waterloo Waterloo, Ontario, Canada
VOLUME XVI
1977
ACADEMIC PRESS
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SAN FRANCISCO
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Library of Congress Cataloging i n Publication Data Manske, Richard Helrnuth Fred, The alkaloids. Vols. 8-16 edited by R. H. F. Manske. Includes bibliographical references. 1. Alkaloids. 2. Alkaloids-Physiological effect. I. Holrnes, Henry Lavergne, joint author. 11. Title: 1. Alkaloids. QV628 M288al Thru physiology. [DNLM: QD421.M3 547 '.I 2 50-5522 ISBN 0-12-469516-7
PRINTED IN THE UNITED STATES OF AMERICA
CONTENTS
LIST OF CONTRIBUTORS.. ....................................................

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OF PREVIOUS VOLUMES.. .......................................... CONTENTS
ix xi xiii
Chapter 1. Plant Systematics and Alkaloids S. SEIGLER DAVID
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Data to Be Utilized . . . . .......................................... UI. Application of the Data t iological Problems ........................ 1V. Alkaloids in Lower Vascular Plants and Gymnosperms . . . . . . . V. Alkaloids in the Angiosperms . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 3 8
73
Chapter 2. The Tropane Alkaloids L. CLARKE ROBERT
I. Introduction ... 11. New Tropane A1
.......... ..........
..............
..........
...........
IX. Analytical Methods
References .........................
107
.......... ...............
..........
..........
153
Chapter 3. Nuphar Alkaloids JERZY T. W R ~ B E L
I. Introduction . . . . . . .
11. 111. IV. V. VI.
.....
181
C,, Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sulfur-Containing C,, Alkaloids . . . . . . . . . . . . . . . Mass Spectrometry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Total Synthesis of C,, Nuphar Alkaloids . . . . . . . ............... Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211 213
.....
V
..............................
vi
CONTENTS
Chapter 4. Celestraceae Alkaloids ROGER M. SMITH I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Occurrence and Isolation . . .
t.......
215
........... ... . . . . . . . 216 Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 111. Structures of Esters of Nicot IV. Structures of Diesters of Substituted Nicotinic Acids, . . . . . . . . . . . . . . . . . . . . 227
V. Structures of Related Sesquiterpene ............................. VI. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . VII. Biological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
241 245 246 246
Chapter 5. The Bisbenzylisoquinoline A l k a l o i d s Occurrence, Structure, and Pharmacology K. T. BUCK, and K. L. STUART M. P. CAVA, I. 11. 111. IV. V. VI . VII . VIII. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure Revisions . . . . . . . . . ......................... ............. New Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Known Alkaloids from New Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................... Methods and Techniques . . . ................... Pharmacology . . . . . . . . . . . . Bisbenzylisoquinoline Alkal ated by Molecular Weight.. . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . Appendix . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
250 251 257 297 297 300 301 304 312
Chapter 6. Syntheses of Bisbenzylisoquinoline Alkaloids MAURICE SHAMMA and VASSIL ST. GEORGIEV 11. 111. IV. V. VI. VII. VIII. IX.
319 I. Introduction . . . . . . . . . . . . . . . . .......................... Dauricine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Magnolamine-Type Alkaloids ............................ 336 Berbamine-Oxyacanthine-Type _ . . . . . . _ . . . . . 341 Thalicberine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
X.
XI. XK XIII. XIV.
Trilobine-Isotrilobine-TypeA Menisarine-Type Alkaloids . . Tiliacorine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . Liensinine-Type Alkaloids . . . Curine-Chondocurine-Type Alkaloids ......................... _................. Miscellaneous Syntheses . . . . . . . . . . . . . . . . . . . . . . . Syntheses Using Phenolic Oxidative Coupling . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis Using Electrolytic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Pentafluorophenyl Cop ............ . ...................
. . . . . . . . ...................
354 357 359 361 363 381 383 387 387 389
CONTENTS
Chapter 7. The Hasubanan Alkaloids INUSUSHI and TOSHIRO IBUKA YASUO I. 11. III. IV. V. VI. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Occurrence and Physical Constants of the Hasubanan Structure Elucidations . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . Synthesis of the Hasubanan Skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of Hasubanan Alkaloids .......................... ... Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . .. . . ....................................
vii
393 395 395 414 419 427 428
Chapter 8. The Monoterpene Alkaloids GEOFFREY A. CORDEU I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Isolation and Structure Elucidation of the Monoterpene Alkaloids . . . . . . 111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids . . . . . . . . . . . . . IV. Pharmacology of the Monoterpene Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Summary ........................................................... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
432 432 470 499 502 502
Chapter 9. Alkaloids Unclassified and of Unknown Structure R. H. F. MANSKE I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Plants and Their Contained Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUBJECTINDEX... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
511 511 551
557
LIST OF CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors contributions begin.
K. T. BUCK,Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania (249) M. P. CAVA,Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania (249) ROBERT L. CLARKE, Sterling-Winthrop Research Institute, Rensselaer, New York (83) GEOFFREY A. CORDELL, Department of Pharmacognosy and Pharmacology, College of Pharmacy, University of Illinois at the Medical Center, Chicago, Illinois (431) VASSILST. GEORGIEV, USV Pharmaceutical Corporation, Tuckahoe, New York (319) TOSHIRO IBUKA, Department of Pharmaceutical Sciences, Kyoto University, Sakyo-ku Kyoto, Japan (393) YASUO INUBUSHI, Department of Pharmaceutical Sciences, Kyoto University, Sakyo-ku Kyoto, Japan (393) R. H. F. MANSKE, Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada (511) DAVID S. SEIGLER: Department of Botany, The University of Illinois, Urbana, Illinois (1) MAURICE SHAMMA, Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania (319) ROGER M. SMITH, School of Natural Resources, The University of the South Pacific, Suva, Fiji (215) K. L. STUART, Department of Chemistry, University of the West Indies, Kingston, Jamaica (249) JERZY T. WR~BEL, Department of Chemistry, University of Warsaw, Warsaw, Poland (181)
* Present address: Calle Peria 3166-9A, Buenos Aires, Argentina.
ix
PREFACE
The literature dealing with alkaloids shows no obvious signs of abatement. The classic methods of the organic chemist employed in structural determinations have evolved into spectral methods, and chemical reactions are involved largely in confirmatory and peripheral studies. Inasmuch as the spectral methods have become largely standardized we incline to limit the details in these volumes. Many new and already known alkaloids have been isolated from new and from previously examined sources. Novel syntheses are a prominent feature of recent publications. We attempt to review timely topics related to alkaloids.
R. H. F. MANSKE
x 1
CONTENTS OF PREVIOUS VOLUMES
Contents of Volume I
CHAPTER 1. Sources of Alkaloids and Their Isolation BY R . H . F . MANSKE . . . . . . . 2 . Alkaloids in the Plant BY W . 0. JAMES 3 . The Pyrrolidine Alkaloids BY LEOMARION . . . . . . 4 . Senecio Alkaloids BY NEISON J . LEONARD . . . . . . 5. The Pyridine Alkaloids BY LEOMARION . . . . . . 6. The Chemistry of the Tropane Alkaloids BY H . L . HOLMES . 7. The Strychnos Alkaloids BY H . L . HOLMES . . . . . .
. . .
. . . . . .
. . .
. . .
. . . . . .
1 15 91 107 165 271 375
Contents of Volume 1 1
8.1. 8.11. 9. 10.
11. 1 2. 13. 14. 15.
1 The Morphine Alkaloids I BY H . L . HOLMES . . . . . . . . The Morphine Alkaloids BY H . L . HOLMES AND (IN PART) GILBERT STORK161 Sinomenine BY H . L . HOLMES . . . . . . . . . . . . 219 Colchicine BY J . W . COOK AND J . D . LOUDON . . . . . . . . 261 . 331 Alkaloids of the Amaryllidaceae BY J . W . COOK AND J . D . LOUDON . Acridine Alkaloids BY J . R . PRICE . . . . . . . . . . . 353 The Indole Alkaloids BY LEOMARION . . . . . . . . . . 369 The Erythrina Alkaloids BY LEOMARION . . . . . . . . . 499 The Strychnos Alkaloids . Part 1 1BY H . L . HOLMES . . . . . . 513
Contents of Volume III

16. The Chemistry of the Cinchona Alkaloids BY RICHARD B . TURNER AND R. B. WOODWARD . . . . . . . . . . . . . . . 17. Quinoline Alkaloids Other than Those of Cinchona BY H . T . OPENSHAW 18. The Quinazoline Alkaloids BY H . T. OPENSHAW . . . . . . . 19. Lupine Alkaloids BY NELSON J . LEONARD . . . . . . . . . 20 . The Imidazole Alkaloids BY A . R . BATCERSBY AND H . T . OPENSHAW . . 21 . The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOG AND 0. JEGER . . . . . . . . . . . . . . . . . . 22 . P-Phenethylamines BY L . RETI . . . . . . . . . . . . 23. Ephreda Bases BY L . RETI . . . . . . . . . . . . . 24 . TheIpecac Alkaloids BY MAURICE-MARIE JANOT . . . . . . .
1 65 101 119 201
247 313 339 363
Contents of Volume N
25 . 26. 27. 28 .
The Biosynthesis of Isoquinolines BY R . H . F . MANSKE Simple Isoquinoline Alkaloids BY L. RETI . . . . Cactus Alkaloids BY L . RETI . . . . . . . . The Benzylisoquinoline Alkaloids BY ALFRED BURGER
. . . .
. . . .
. . . . . . . . . . . .
1 7 23 29
xiii
XiV
CHAPTER 29. The Protoberberine Alkaloids BY R . H . F . MANSKE AND WALTER R. ASHFORD . . . . . . . . . . . . . . . . . . . . . . . . . 30 . The Aporphine Alkaloids BY R . H . F. MANSKE 31 . The Protopine Alkaloids BY R. H . F. MANSKE . . . . . . . . 32. Phthalideisoquinoline Alkaloids BY JAROSLAV STANEK AND R. H . F . MANSKE . . . . . . . . . . . . . . . . . . 33 . Bisbenzylisoquinoline Alkaloids BY MARSHALL KULKA . . . . . 34 . The Cularine Alkaloids BY R. H . F . MANSKE . . . . . . . . 35 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . 36 . The Erythrophleum Alkaloids BY G. DALMA . . . . . . . . 37 . The Aconitum and Delphinium Alkaloids BY E . S. STERN . . . .
77 119 147 167 199 249 253 265 275
Contents of Volume V
38 . 39. 40. 41 . 42 . 43 . 44 . 45 . 46 . 47 . 48 .
Narcotics and Analgesics BY HUGO KRUEGER . . . . . . . . Cardioactive Alkaloids BY E . L. MCCAWLEY . . . . . . . . Respiratory Stimulants BY MICHAEL J . DALLEMAGNE . . . . . Antimalarials B Y L. H . SCHMIDT . . . . . . . . . . . . Uterine Stimulants BY A . K . REYNOLDS . . . . . . . . . Alkaloids as Local Anesthetics BY THOMAS P. CARNEY . . . . . Pressor Alkaloids BY K . K . CHEN . . . . . . . . . . . Mydriatic Alkaloids BY H. R . ING . . . . . . . . . . . Curare-like Effects BY L . E . CRAIG . . . . . . . . . . . The Lycopodium Alkaloids BY R . H . F . MANSKE . . . . . . . Minor Alkaloids of Unknown Structure BY R . H . F . MANSKE . . .
1 79 109 141 163 211 229 243 265 259 301
Contents of Volume VI
1. 2. 3. 4. 5.
6.
7. 8. 9.
Alkaloids in the Plant BY K . MOTHES . . . . . . The Pyrrolidine Alkaloids BY LEOMARION . . . . . Senecio Alkaloids BY NELSON J. LEONARD . . . . . The Pyridine Alkaloids BY LEOMARION . . . . . The Tropane Alkaloids BY G . FODOR . . . . . . The Strychnos Alkaloids BY J . B . HENDRICKSON . . . The Morphine Alkaloids BY GILBERT STORK . . . . Colchicine and Related Compounds BY W . C . WILDMAN . Alkaloids of the Amaryllidaceae BY W. C . WILDMAN . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 31 35 123 145 179 219 247 289
Contents of Volume VII

10. 11 . 12. 13. 14. 15 . 16. 17 .
The Indole Alkaloids BY J . E . SAXTON . . . . . . . . . . The Erythrina Alkaloids BY V . BOEKELHEIDE . . . . . . . . Quinoline Alkaloids Other than Those of Cinchona BY H . T . OPENSHAW The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . Lupine Alkaloids BY NEWON J . LEONARD . . . . . . . . . Steroid Alkaloids: The Holarrhena Group BY 0. JEGER AND V . PRELOG Steroid Alkaloids: The Solanum Group BY V . PRELQG AND 0. JEGER . . Steroid Alkaloids: Veratrum Group BY 0. JEGER AND V . PRELOG . .
1 201 229 247 253 319 343 363

CHAFTER . . . . . . . . 18. The Ipecac Alkaloids BY R . H . F . MANSKE 19. Isoquinoline Alkaloids BY R . H . F . MANSKE . . . . . . . . 20. Phthalideisoquinoline Alkaloids BY JAROSLAV STAN~K . . . . . 21 . Bisbenzylisoquinoline Alkaloids BY MARSHALL KULKA . . . . . 22 . The Diterpenoid Alkaloids from Aconitum, Delphinium, and Garrya Species BY E . S. STERN. . . . . . . . . . . . . . 23 . The Lycopodium Alkaloids BY R . H . F . MANSKE . . . . . . . 24 . Minor Alkaloids of Unknown Structure BY R . H . F . MANSKE . . .
xv
419 423 433 439 473 505 509
Contents of Volume VIII

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
. . . . . . . . . . . The Simple Bases BY J . E . SAXTON Alkaloids of the Calabar Bean BY E . COXWORTH . . . . . . . The Carboline Alkaloids BY R . H . F . MANSKE . . . . . . . . The Quinazolinocarbolines BY R . H . F. MANSKE . . . . . . . Alkaloids of Mitragyna and Ourouparia Species B Y J . E . SAXTON . . Alkaloids of Gelsemium Species BY J . E . SAXTON . . . . . . . Alkaloids ofPicralima nitida BY J. E . SAXTON . . . . . . . . Alkaloids ofAlstonia Species BY J . E . SAXTON. . . . . . . . The Zboga and Voacanga Alkaloids BY W . I . TAYLOR . . . . . . The Chemistry of the 2,2'-Indolylquinuclidine Alkaloids BY W . I . TAYLOR The Pentaceras and the Eburnamine (HunteriabVicamine Alkaloids BY W . I . TAYLOR . . . . . . . . . . . . . . . . 12. The Vinca Alkaloids BY W . I . TAYLOR . . . . . . . . . . 13. RauwolfiaAlkaloids with Special Reference to the Chemistry of Reserpine
1 27 47 55 59 93 119 159 203 238
250 272
BYE . SCHLITTLER . . . . . . . . . . . . . . . 287 14. The Alkaloids ofdspidosperma, Diplorrhyncus,Kopsia, Ochrosia, Pleioc a r p , and Related Genera BY B . GILBERT . . . . . . . . 336 15. Alkaloids of Calabash Curare andStrychnos Species BY A . R . BATTERSBY . . . . . . . . . . . . . . 515 AND H . F . HODSON . 16. The Alkaloids of Calycanthaceae BY R . H . F. MANSKE . . . . . 581 17 . Strychnos Alkaloids BY G. F . SMITH . . . . . . . . . . . 592 18. Alkaloids ofHaplophyton cimicidum BY J . E . SAXTON . . . . . 673 AND W . 19. The Alkaloids of Geissospermum Species BY R . H . F. MANSKE ASHLEY HARRISON . . . . . . . . . . . . . . . 679 20 . Alkaloids ofPsuedocinchona and Yohimbe BY R . H . F . MANSKE . . 694 AND A . HOFMA" . . . . . . 726 21 . The Ergot Alkaloids BY A . STOLL 22 . The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR . . . . . . 789
Contents of Volume IX
1 . 2. 3. 4.
1 The Aporphine Alkaloids BY MAURICE SHAMMA . . . . . . . 41 TheProtoberberine Alkaloids BY P . W . JEFFS . . . . . . . . Phthalideisoquinoline Alkaloids BY JAROSLAV S T A N ~ K . . . . . 117 Bisbenzylisoquinoline and Related Alkaloids BY M . CURCUMELLIRODWTAMO AND MARSHALL KULKA . . . . . . . . . . 133 5 . Lupine Alkaloids BY FERDINAND BOHLMANN AND DIETERSCHUMANN 175 6 . Quinoline Alkaloids Other than Those of Cinchona BY H. T . OPENSHAW 223
xvi
CHAPTER 7 . The Tropane Alkaloids BY G . FODOR . . . . . . . . . . 269 8 . Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V. ERN+ AND F . SORM. . . . . . . . . . . . . . . . . 305 9 . The Steroid Alkaloids: The Salamandra Group BY GERHARD HABERMEHL427 10. Nuphar Alkaloids BY J . T. WROBEL . . . . . . . . . . . 441 11. The Mesembrine Alkaloids BY A . POPELAK AND G. LETFENBAUER . . 467 12. The Erythrina Alkaloids BY RICHARD K. H I L L . . . . . . . . . 483 13. Tylophora Alkaloids BY T . R . GOVINDACHARI . . . . . . . . 517 14. The Galbulimima Alkaloids BY E . RITCHIE AND W. C . TAYLOR . . . 529 15. The Stemona Alkaloids BY 0 . E . EDWARDS. . . . . . . . . 545
Contents of Volume X
1. Steroid Alkaloids: The Solanun Group BY KLAUS SCHRIEBER. . . 1 2 . The Steroid Alkaloids: The Veratrum Group BY S . MORRIS KUPCHAN AND ARNOLDW.BY . . . . . . . . . . . . . . . . 193 3 . Erythrophleum Alkaloids BY ROBERT B . MORIN . . . . . . . 287 4 . The Lycopodium Alkaloids BY D . B . MACLEAN . . . . . . . . 306 5. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . 383 6. The Benzylisoquinoline Alkaloids BY VENANCIO DEULOFEU, JORGE COMIN. AND MARCELO J . VERNENGO . . . . . . . . . . 402 7 . The Cularine Alkaloids BY R . H . F. MANSKE . . . . . . . . 463 8 . Papaveraceae Alkaloids BY R . H . F. MANSKE . . . . . . . . 467 9 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . 485 10. The Simple Indole Bases BY J . E . SAXTON . . . . . . . . . 491 11. Alkaloids of Picralima nitida BY J . E . SAXTON . . . . . . . . 501 12. Alkaloids of M i t m g y m and Ourouparia Species BY J . E . SAXTON . . 52 1 13. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 545 14. The Taxus Alkaloids BY B . LYTHGOE . . . . . . . . . . 597
Contents of Volume XI
The Distribution of Indole Alkaloids in Plants BY V . SNIECKUS . . . I The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR . . . . . . 41 The 2,2-Indolylquinuclidine Alkaloids BY W . I. TAYLOR . . . . . 73 The Iboga and Voacanga Alkaloids BY W . I . TAYLOR . . . . . . 79 The Vinca Alkaloids BY W. I . TAYLOR . . . . . . . . . . 99 The Eburnamine-Vincamine Alkaloids BY W. I . TAYLOR . . . . . 125 Yohimbirw and Related Alkaloids BY H . J . MONTEIRO . . . . . 145 Alkaloids of Calabash Curare and Strychnos Species BY A . R . BATTERSBY ANDH . F . HODSON . . . . . . . . . . . . . . . 189 9 . The Alkaloids of Aspidosperma, Ochrosia, Pleiocarpa, Melodinus, and Related Genera BY B . GILBERT . . . . . . . . . . . 205 10. The Amaryllidaceae Alkaloids BY W . C. WILDMAN . . . . . . 307 A N D B. A . PURSEY 11. Colchicine and Related Compounds BY W . C. WILDMAN 407 12. The Pyridine Alkaloids BY W . A . AYER AND T . E . HABGOOD. . . . 459
1. 2. 3. 4. 5. 6. 7. 8.
xvii
Contents of Volume XI1

CHAFTER The Diterpene Alkaloids: General Introduction BY S. W. PELLETIER AND L. H. KEITH . . . . . . . . . . . . . . . . . . 1. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species: The C,,-Diterpene Alkaloids BY S. W. PELLETIER AND L. H. KEITH 2. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species: The Go-DiterpeneAlkaloids BY S. W. PELLETIER AND L. H. KEITH 3. Alkaloids ofAlstonia Species BY J. E. SAXTON. . . . . . . . 4. Senecio Alkaloids BY FRANK L."WARREN . . . . . . . . . 5. Papaveraceae Alkaloids BY F. SANTAVY . . . . . . . . . 6. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 7. The Forensic Chemistry of Alkaloids B Y E .G. C. CLARKE . . . . xv
2 136 207 246 333 455 514
Contents of Volume XIII

1 The Morphine Alkaloids BY K. W. BENTLEY . . . . . . . . The Spirobenzylisoquinoline Alkaloids BY MAURICE SHAMMA . . . 165 The Ipecac Alkaloids BY A. BROSSI, S. TEITEL, AND G. V. PARRY . . . 189 Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . 213 The Galbulirnima Alkaloids BY E. RITCHIEAND W. C. TAYLOR . . . 227 The Carbazole Alkaloids BY R. S. KAPIL . . . . . . . . . 273 Bisbenylisoquinoline and Related Alkaloids BY M. CURCUMELLI-RODC+ STAMO . . . . . . . . . . . . . . . . . . . 303 8. The Tropane Alkaloids BY G. FODOR . . . . . . . . . . . 351 9. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 397 1. 2. 3. 4. 5. 6. 7.
Contents of Volume X N
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Steroid Alkaloids: The Veratrum and B w u s Groups BY J. TOMKO AND 1 2. VOTICKP . . . . . . . . . . . . . . . . . 83 Oxindole Alkaloids BY JASJIT S. BINDRA . . . . . . . . . Alkaloids of Mitragym and Related Genera BY J. E. SAXTON . . . 123 Alkaloids ofPicralima and Alstonia Species BY J . E. SAXTON . . . 157 The Cinchona Alkaloids BY M. R. USKOKOVIC AND G. GRETHE . . . 181 The Oxoaporphine Alkaloids BY MAURICE SHAMMA AND R. L. CASTENSON 225 Phenethylisoquinoline Alkaloids BY TETSUJIKAMETANI AND MASUO KOIZUMI . . . . . . . . . . . . . . . . . . 265 Elaeocarpus Alkaloids BY S. R. JOHNS AND J. A. LAMBERTON . . . 325 The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . . . 347 TheCancentrine Alkaloids BY RUSSELLRODRIGO . . . . . . . 407 The Securinega Alkaloids BY V. SNIECKUS . . . . . . . . . 425 Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 507
xviii
Contents
of
Volume X V
CHAPTER 1. The Ergot Alkaloids BY P. A. STADLER AND P. SWTZ . . . . . . 1 2. The Daphniphyllum Alkaloids BY SHOSUKE YAMAMURA AND YOGHIMASAHIRATA . . . . . . . . . . . . . . . . 41 3. The Amaryllidaceae A l k a l o i d s ~ CIAUDIOFUGANTI ~ . . . . . . 83 AND E. U. KAUBMANN 165 4. The Cyclopeptide Alkaloids BY R. TSCHESCHE 5. The Pharmacology and Toxicology of the Papaveraceae Alkaloids BY V . PREININCER . . . . . . . . . . . . . . . 207 6. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 263
-CHAPTER
1-
PLANT SYSTEMATICS A N D ALKALOIDS

DAVID S. SEICILER
The University of I ~ ~ i n o i s Urbana, Illinois
I. Introduction ........................................................ A. What Is Plant Systematics ? ....................................... B. Major Goals of Plant Systematics .................................. 1 1 . Data to Be Utilized ................................................. A. Relationship of Chemical Data to Botanical Data .................... B. Rationale for Using Chemical D a t a . . ............................... C. Botanical and Chemical Literature ................................. D. Documentation of Plant Materials. . . . . . . . . . 1 1 1 . Application of the Data to Biological Problems . A. Nature and Sources of Variation in Plants. .. B. Basic Pathways of Alkaloid Biosynthesis .... IV. Alkaloids in Lower Vascular Plants and Gymnos V. Alkaloids in the Angiosperms ......................................... A. Introduction ..................................................... B. The Magnoliopsida (Dicotyledonous Plants) .......................... ida (Monocotyledonous Plants) ...........................
2 2 3 3 3
6 7
......................................................
I. Introduction
8 8 14 20 22 22 24 65 73
Many scientists, both chemical and biological, have sought to correlate chemical characters (i.e., the presence of certain types of compounds) with various botanical entities. I n the past, several factors have limited the success of such efforts, and it is only in recent years that such correlations have been applied to many plant groups. My purpose in this article is to review several of these earlier attempts as well as to examine current thinking in this area of endeavor. Several new ideas concerning the placement of selected plant groups within taxonomic systems will be discussed, and in addition, certain enigmatic problems that as yet cannot be clearly resolved will be posed as subjects for future investigation. As background t o these discussions, I will first describe the nature and goals of plant systematics t o provide the reader with the necessary perspective to understand the needs of that science.
DAVID S. SEIOLER
A. WHATIs PLANT SYSTEMATICS ? Systematics is the scientific study of the kinds and diversity of organisms and of the relationships between them ( 1 ) .I n former times, much systematic work was based on the examination of preserved herbarium specimens in an effort to describe and classify various plant taxa (a term indicating taxonomic entities of unspecified rank). These studies frequently involved an examination of the form and structural features of relatively small numbers of specimens. Although this approach is still viable in many tropical areas of the world where rich and unstudied floras are in immediate danger of destruction or extreme modification (2, 3), it is largely being supplanted by examination of larger numbers of plants from living populations in temperate areas of the world, where the floras are better known. By means of this latter method, often called biosystematics, one attempts to study as much of the biology of the plant as possible and utilize these data to clarify the taxonomic and evolutionary relationships of the taxa involved ( 4 ) . The information derived from both approaches is normally utilized in two ways: to prepare floras of a particular region (often a state or large natural geographic region) or to account for all the species within a given group-for example, a genus or a family, regardless of where the plants grow ( 5 ) . Although each of the above aspects of systematics assists in identification and location of plant materials this information may also be invaluable to workers in many other fields such as chemistry, ecology, forestry, horticulture, floriculture, genetics, agronomy, zoology, entomology, or pharmacognosy, because of its predictive nature. Despite the introduction of many new approaches and technological advances, the basic systems of taxonomy that have been used for the last two centuries have not changed radically nor are they likely to undergo substantial modification. Movement of certain groups within the systems has occurred frequently. I n this chapter, the system proposed by Cronquist ( 6 )will be used as a basis for discussion, although frequent reference will be made to a number of other contemporary systems. Several of these systems (at the level of family and above) have recently been compared by Becker in Radford et al. ( 5 ) , and reference to that work will prove useful in understanding many taxonomic problems that will be discussed.
B. MAJORGOALSOF PLANT SYSTEMATICS I n summary, the principal goals of plant systematics are to (a) provide a convenient method of identifying, naming, and describing
1.
PLANT SYSTEMATICS
plant taxa, (b) provide an inventory of plant taxa via local, regional, and continental floras, and (c) provide a classification scheme that attempts to express natural or phylogenetic relationships and t o provide an understanding of evolutionary processes and relationships ( 5 ) .In the subsequent parts of this chapter, I will present and discuss ways in which chemical data and in particular alkaloid chemical data can be utilized in meeting these goals.
1 1 . Data to Be Utilized
A. RELATIONSHIP OF CHEMICAL DATA TO BOTANICAL DATA

As both morphological and chemical features are determined by genetics, the structure of a molecule must be as much a character as any other (7). Further, all the characters of a plant must be related and self-consistent. Thus, it is scarcely surprising that new cytological, numerical, and chemical data have provided valuable complementary information about the placement of groups within the taxonomic system rather than upsetting the results of extensive morphological investigations. How did these two types of characters arise and how do they differ Z I n the course of evolution the fate of any change in the genetic material of an organism will in large part depend on the function of the products produced. For example, changes in respiratory proteins, such as cytochromes, are unlikely t o survive, whereas changes in the enzymes that produce alkaloids or other secondary metabolic products are more likely to persist. The evolution of morphological and chemical features of an organism must be interrelated, but significantly, the forces of natural selection do not have the same effect on each type of genetic expression. These differences in selection are very important from a systematic standpoint because evolution of chemical constituents differs from morphological evolution, making the examination of both morphological and chemical characters an extremely valuable approach to the study of evolutionary problems (8).Because the structure of any compound is determined by a series of biosynthetic steps, each of which is under differing selective forces, not only may the structure of the compound itself be useful, but the biochemical pathway by which i t has arisen may be of systematic significance.
FOR USING CHEMICAL DATA B. RATIONALE The two major groups of compounds that have been applied to t,axonomic problems involve basically different approaches and appear
DAVID S . SEIGLER
t o be useful in different manners. To date, these applications involve niacromolecules (in particular proteins) and micromolecules (mostly secondary metabolic compounds such as terpenes, flavonoids, alkaloids, cyanogenic and other glycosides, amino acids, and lipids of various types). When one utilizes macromolecules, he is examining the primary products of plant DNA and changes in amino acids within the protein reflect changes in the base sequence of the DNA. Initial studies of protein sequencing, especially those studies involving cytochrome C, indicate that this data provides valuable information about phylogeny and relationships a t the higher taxonomic categorical levels (families, orders, classes). Cytochrome c, which occurs in both animals and plants, has been sequenced in several species of animals (9). The fossil record for animals generally confirms information derived from these phylogenetic studies. The number of similarities in amino acids in particular positions in cytochrome c molecules from different animals makes it statistically improbable that they could have arisen from more than a single ancestral type with an ancestral cytochrorne c molecule. By tracing the differences in amino acid substitutions it is possible t o relate various groups of animals, as successive groups after a modification carry the changed cytochrome c molecule. I n plants, especially flowering plants, there is no extensive fossil record and much of the current knowledge of relationships and phylogeny in this group is based on extrapolation of studies of morphological data. To date, relatively few plant cytochromes have been studied, but in the few that have been investigated, it is apparent from the number of similarities of amino acid sequences that plant and animal G Y ~ O chromes are related. It is also evident that the sequences of amino acids in genera of the same family me more similar to each other than to those of other families and that families thought to be closely related by morphological evidence generally resemble each other more closely than less related families. The evolutionary history of plant groups, as well as of animals, appears t o be recorded in this and other proteins. Much recent work has established that micromolecular chemical data can also provide valuable insight into evolutionary processes ( 8 ) . Chemical studies of secondary products have proved useful in resolving many problems of specification and evolution but in contrast to protein sequencing data have generally been applied to the study of lower taxonomic categories, i.e., problems a t the species and genus level (10, 11). However, as will be pointed out, they may also be of value a t higher taxonomic levels. To understand how secondary compounds can be useful for the study
1. PLANT SYSTEMATICS
of systematic problems, it is necessary to consider how and why they arose. Plants have a multitude of proteinaceous materials, many of which have enzymatic functions. In primitive organisms these compounds were and are largely active in synthesizing primary metabolic components of cells. As these organisms evolved, genetic material and its derived proteins were duplicated and increased both in amount and in redundancy. Mutations occurred that subsequently produced changes in the proteins and their products. The forces of natural selection operated on all such products (12), selecting them for value to and compatibility with parental organisms and the ecological systems in which they occur. Many of these compounds were of a less critical nature than primary metabolites and were less widely distributed. Complications are introduced because one does not observe the primary gene products, but rather pools of compounds they produce, the concentrations of which are partially functions of the relative amounts and activities of enzymes, the availability of certain precursors, and compartmentalization and translocation with the cell ( 4 ) . Subsequent mutations may affect steps in a biosynthetic sequence that we observe as an accumulation or disappearance of an altered product. These mutations usually involve the loss, gain, blockage, or alteration of the specificity of an enzyme system. Loss of synthetic ability is presumably more common than gain or alteration, since it merely implies destruction or blocking of a process instead of setting up a new one ( 7 ) . This is partially confirmed by the observation that in several groups of species from the related genera Parthenium, Hymenoxys, and Ambrosia of the Compositae, more highly evolved members have simplified patterns of secondary compounds (13).A one-gene loss may also block an entire pathway. The determination of homologous origin of similar compounds in different taxonomic groups is one of the fundamental problems inherent in the taxonomic application of secondary compounds. Two taxa may synthesize or pool the same products by different pathways; therefore, the mere presence of a compound is not necessarily an indication of relationship; i.e., similarities in the chemistry of plant taxa (or morphological features) may reflect an evolutionary or phyletic similarity but may also be the result of convergent evolutionary processes ( 4 ) . With a knowledge of biosynthetic pathways of secondary compounds in plants, it should be possible to determine a t what point in a sequence divergence has occurred and what subsequent changes have come to pass (7). In reality this is rarely realized because of several factors; several classes of compounds do not appear to have specific structural requirements, whereas in others less variation can be tolerated. For example, most phenolic substances could serve as antioxidants or many
DAVID S. SEIGLER
lipid compounds for surface coatings as long as the necessary physical properties are met ; but attractants for specific pollinators or diterpenes with hormonal activities must be precisely synthesized (7). Many plant products arise by simple processes such as removal of activating groups (as phosphate or coenzyme A) or from oxidations, reductions, or methylations of easily modified groups (7). I n some cases the relative amounts of products produced may simply reflect the rates of two enzymes operating on a common precursor. Highly probable reactions, such as the introduction of an hydroxyl group ortho or para to an existing one in a phenol, occur frequently in nature. These types of changes are usually of only minor importance in considering the taxonomic significance of secondary compounds. Other reaction sequences are reversible or are controlled by feedback inhibition controls such that when a given compound disappears it disappears without a trace or causes accumulation of a compound far removed in the sequence. For example, polyketide chains, probably as coenzyme A esters, are rapidly reversible to their initial units unless some chemically irreversible stage is reached such as reduction or cyclization (7). In the fungus Penicillium islandicum which produces polyketide anthraquinones, mutation simply leads to the complete absence of these compounds. We have limited knowledge as to what pathways may be available in advanced plant groups as we can only see the products of those pathways that the plant utilizes a t a particular time. Several lines of work suggest that many plants are capable of carrying out complex reactions or reaction series but lack precursors or particular enzymes under normal situations. For example, when plants of Nicotiana are fed thebaine and certain other precursors of morphine they are able to perform several biosynthetic steps and produce morphine (14) which is not known to occur naturally in the genus. Interestingly, this conversion cannot be made by some species of Papaver, although other species of the genus contain thebaine and morphine. In assessing the importance of a particular change as an evolutionary step it is necessary to decide on the probability of its occurrence. As a general rule, the more difficult the reactions and the less available the building blocks or the more reaction steps required in a definite sequence to give rise to a compound, the rarer will be its convergent formation
(14).
C . BOTANICAL AND CHEMICAL LITERATURE Many earlier publications were based on mass collections of materials, often gathered from large geographical areas and/or of uncertain origin.
1.
PLAXT SYSTEMATICS
Frequently, only the major constituents-those that were poisonous, crystallized readily, or had other easily detectable properties-were examined. These facts must be considered by those who intend to apply the information to a taxonomic problem. Another difficulty in utilizing chemical data from the literature is a lack of reliability of certain structure determinations and in particular the identification of plant products by such physical properties as gas-liquid chromatography retention time, paper and thin-layer chromatography R, values, color reactions, and spot tests. Misidentification of compounds by wet chemical methods is not uncommon in the older literature before advanced spectral methods became available and must always be considered. One of the most serious problems in utilizing literature data is that almost no chemical reports are supported by adequately vouchered plant materials. Proper vouchering records would make it possible to examine the original materials and allow comparison with other collections in order to ascertain whether (a) the material was correctly identified and (b) certain phenomena, such as hybridization, introgression, or subspecific variations exist. It would also permit subsequent workers to determine the presence of fungi, lichens, algae, insects, etc., that may be involved in the production of certain secondary compounds. If a small portion of the actual materials utilized for the research is also preserved, it would permit later analysis for foreign contaminants. I n other cases, careful perusal of the botanical literature will reveal that taxonomists have placed taxa of various rank incorrectly. These incorrect placements may range from questionable or aberrant species in a genus to the realignment of entire orders of plants. Chemical data can assist in resolving problems of this type, but they sometimes provide enigmatic results until sufficient information is available to allow a reassignment of the taxa involved. One must look carefully and critically a t all reported data to be sure both chemical and botanical portions of the work have been done and interpreted correctly before applying the data to a problem under investigation.
D. DOCUMENTATION OF PLANT MATERIALS As mentioned in the preceding section, many early reports of alkaloids and other secondary compounds are suspect because accurate techniques required for assignment of complex structures were not available. Nonetheless, the major problem in using these data for systematic studies is not the reliability of the chemical data but the identity of the plant materials that were examined (15).
DAVID S . SEIGLER
To document the materials used, the investigator should always have a competent person identify his plant materials and a portion should be dried or otherwise preserved as a voucher specimen so that further examination of the specimen is possible should it be desirable. The selected plant should be typical for the population and, when possible, should have mature reproductive organs. Full collection or acquisition data (data, location, collector, habitat, etc.) should be provided and the specimen deposited in a recognized herbarium. Taxonomists usually will be willing to assist with the necessary details of voucher specimen preparation. Most major universities have collections of dried plant specimens (a herbarium) that provide a wealth of data about the ranges, flowering t'imes, uses, soil preferences, and other information about particular species as well as preserving materials for future study or reinvestigation. I n publications describing chemical results, one should record the locations and dates of plant collections, the parts of the plants used in the study, the name of the herbarium where the voucher specimens are deposited, and the name of the taxonomist who identified the plants. With this information and with the possibility of comparing specimens collected a t other times with the original vouchers, later investigators can usually determine the relationship of the plants concerned to the original collection (15, 16).
111. Application of the Data to Biological Problems
A. NATURE AND SOURCES OF VARIATION IN PLANTS

Until sensitive separation techniques (column, paper, thin-layer, and gas chromatography; countercurrent distribution; etc.) and sensitive methods of instrumental analysis (IR, NMR, UV, and mass spectrometry) became available, it was not feasible to undertake the analysis of secondary plant constituents from single plants of most species in naturally occurring populations. These new microtechniques permit the chemist or botanist to obtain chemical data from single plants rapidly, allowing the extension of the biosystematic approach to chemical as well as morphological characters. When phytochemical workers began to examine single plants, they were often frustrated by apparently uninterpretable variations of chemical constituents. Many of these investigators did not do adequate sampling, ignored the significance of these variations, and came to
conclusions based on a meager amount of data in comparison to what was actually needed. Recent combined chemical and morphological investigations have used this information more fully and proved that, instead of being troublesome, the study of chemical and morphological variation actually provides a key to the solution of many problems of biological speciation, hybridization, and introgression.* Relationship between plant taxa is established by summarizing the similarities between groups of organisms and contrasting their differences. We consider two plants to be closely related if they have many common characters and only distantly so (or at higher categorical levels) if the differences outweigh the similarities. In contrast to this, the name of the game in evolution is change and the ability to maintain variability. Few natural populations are without measurable variation; that is, plants from interbreeding groups that share a gene pool have phenotypic and genotypic differences that can be seen even by inexperienced observers. How do these variations arise and how are they maintained ! Each individual plant must possess the ability to respond to its environment, but this variation must remain within the limits set by the genetic makeup of the taxon (12, 17). Thus, phenotypic expression is determined by both genotypic composition and reaction to a specific environment. Some characters are little changed by environment--e.g., leaf arrangement or floral structure-and these have been considered good characters or to be genetically fixed. Other characters are known to vary radically and are said to be phenotypically plastic. Examples of characters of this type are leaf shape, stem height, and time of flowering. The effects of environment are superimposed on and may obscure genotypic variability; further, it is the phenotype produced by both that is is exposed to the pressures of natural selection. Davis and Heywood ( 1 7 ) have listed a number of important physical factors in determining the appearance of a plant in nature. Among these are light, seasonal variation, elevational differences, terrestrial versus epiphytic state, photoperiodism, temperature, temperature periodic effects, water (heterophylly), wind, soil (e.g., halophytes), and biotic factors such as fungal and bacterial infection, ant habitation, galls, grazing and browsing, fire, and trampling. The population is considered by many to be the basic evolutionary * Introgression is the process by which the genes of one taxon are mixed with the
genes of another by hybridization of the two taxa followed by backcrossing of the hybrid plants with either of the two parents. Even when hybrids are not significant in relative numbers, they can allow gene flow and mixing, producing increased variability of the two parental types.
10
DAVID S . SEIGLER
unit and when we discuss speciation and concomitant chemical change it is necessary to understand something of the nature of variation both within and among populations of a given taxon or group of taxa. Populational variations are a function of the variation of individual plants and of the common gene pool that they possess. Morphological and chemical features enable us to recognize the population, but they do not define it. It must also be remembered that the population is a dynamic entity. It changes in numbers of plants and, even in some perennials, in the particular individuals present in a given year. A population may occupy a much larger geographical area in some years than others. It may separate into two or several new populations under some conditions that may be maintained or later merge with the parental population. Taxonomic descriptions are sometimes based on a single plant specimen, which may not reflect the nature of the species or its populations. Several factors are important in determining genetic variation. Mutations usually produce a one-gene change, but these changes may have profound effects. Such changes as zygomorphic corollas t o actinomorphic corollas in Antirrhinum, the gamosepalous to polysepalous condition in Silene, spurred t o nonspurred flowers in Aquilegia, and annual to biennial condition in Atropa are all known to be controlled by one gene ( 1 7 ) . Most mutations affect several characteristics of the phenotype. Thus, a species may differ from another in several characters but still may be separated by only a one gene difference. Characters that have no selective advantage in themselves can become established through the secondary effects of genes that have been selected as valuable to the organisms for completely different reasons ( 1 7 ) .Certain genetic variants coexist in temporary or permanent equilibrium within a single population in a single spatial region in a phenomenon known as polymorphism ( 1 7 ) . Recombination of genetic variability in populations is largely determined by the breeding system. Cross-fertilized populations contain a large store of variability hidden in the form of recessive genes in the heterozygous condition. This variability serves as insurance in the presence of a constantly changing environment. I n sexual populations breeding tends to take place principally between neighboring individuals. I n summary, the three factors that largely control variation in populations are (a) external environmental modification, (b) mutation, and (c) genetic recombination ( 1 7 ) . Populations rarely stay the same over a period of time but are affected by the process of natural selection in a stabilizing, disruptive, or directional manner. Populations separated by geographical, ecological, or reproductive barriers will tend to differ-
1.
PLANT SYSTEMATICS
11
entiate into a series of populations that may have gradually accrued differences (clinal variation) or stepwise variations associated with ecological differences (ecotypic variation) (17). If the differences between populations increases sufficiently, and especially if reproductive barriers arise, these differentiating populations may be recognized as species. Stebbins ( 1 2 ) considers four major factors in speciation: (a) mutation, (b) genetic recombination, (c) natural selection, and (d) isolation. I n small, often peripheral populations, chance may play a greater role in speciation because the probability of loss of a particular character is greater; recessive genes are more likely to appear and become homozygous, and the genetic nature of the population may be determined by the founders or survivors of a period of catastrophic selection. These phenomena explain many of the variational patterns observed in the distribution and occurrence of secondary plant compounds, especially at the lower taxonomic ranks, and although they have mostly been examined by means of morphological characters, much evidence suggests that evolution and speciation may be studied or measured by chemical characters as well. I n the preceding discussion, variation of morphological characters has been considered. There is no reason t o think that variation in chemical characters has not occurred and is not maintained in a similar manner. I n contrast to morphological features, however, the specific structures and steps of biosynthetic pathways are easier to quantify and generally simpler in terms of genetic control (at least in principle). Secondary compounds are affected by environmental as well as genetic factors (18, 19). In a study of alkaloids of the genus Baptisia (Leguminosae), Cranmer studied the variation of lupine alkaloids during the development of individual plants in different populations of Baptisia leucophaea Nutt. ( 2 0 ) . Individual plants in each population exhibited considerable quantitative variation, while plants from different populations were similar at similar stages of development. However, there was striking variation in the specific alkaloids produced, the relative amounts of each, and in the total quantity of alkaloids present a t any given time in development. Nowacki encountered similar variation in lupine alkaloids in the genus Lupinus ( 2 1 ) . A number of workers have examined the genetics of alkaloid production by the study of hybrid plants (14, 21-25). These results indicate that the genetic mechanisms that control alkaloid synthesis are complex and that hybridization and introgression can produce significant variations in the alkaloid content of plants within a population. Many past workers have been unaware of natural hybridization and, because these plants are occasionally indistinguishable from the parental species,
12
DAVID S . SEIGLER
have not been able t o interpret the alkaloid patterns observed (14, 15). Hybridization and introgression in the genus Baptisia has been extensively studied by workers a t the University of Texas. Several populations that contained all possible hybrid combinations, plants derived from back-crossing these plants with the parental plants, and the parental plants were examined. The status of these plants was established by independent methods; subsequently the alkaloid chemistry was examined. The data indicated that the hybrid plants not only failed to exhibit the alkaloid chemistry of the parent species either singly or combined, but also showed some striking quantitative variation among individual hybrid plants. Mabry concludes that this variation is extremely useful and represents one of the best available techniques for detecting and documenting natural hybridization and introgression (26). Extensive variation can occur in the different parts of an individual plant ( 2 7 ) . Changes associated with the reproductive parts of a plant are often striking; these organs also exhibit the greatest amount of morphological change during a plants growth and development. Cranmer and co-workers (20, 28) observed that in Baptisia species alkaloids often showed greater variation between organs of plants from a single species than between the same organs for different species. The total yield of alkaloids from different organs was also shown t o vary significantly. The most thoroughly investigated plants in this regard are medicinally important ones such as Papaver somniferum L. and solanaceous plants of the genera Nicotiana, Atropa, Hyoscyamus, and Datum (27). At the present time our lack of knowledge of the specific enzymology of the synthesis of secondary metabolites prevents direct comparison of many of the pathways involved in various taxa. Examination and comparisons must frequently be restricted t o those systems ascertained t o be related by other reasoning, such as a knowledge of the structures of other compounds derived from and part of the biosynthetic pathways in the same and related species of plants. Secondary compounds have classically been viewed as waste or excretion products ( l a ) ,but a body of information is accumulating that suggests that many have important coevolutionary defensive and attractive roles (29-31) as well as primary metabolic importance (32-34). The forces of natural selection seldom operate on a single organism but on a total biological system. This is undoubtedly one reason convergence in the evolution of both morphological and chemical characters is observed. It is well known, for example, that certain habitats are occupied by
1.
PLANT SYSTEMATICS
13
plants that possess similar morphological features (12, 27, 35-38). It has not been definitely established, but it appears that various chemical components of plants can be seiected to produce convergence of chemical types. One example that confirms this possibility is that Ammodendron conollyi Bge., a legume native to Central Asia, contains the alkaloids ammodendrine (1)and sparteine (2), and another plant from
COCH,
1
that area, Anabasis aphylla L., a member of the Chenopodiaceae, aphyllin (a), and anabasin contains similar alkaloids such as lupinine (3), ( 5 ) .I n the legume, cadaverine (and hence lysine) serves as a precursor
0
3
4 5
for both types, whereas in Anabasis, the quinolizidine alkaloids are formed as in legumes but anabasine is derived from nicotinic acid as in Nicotiana. Thus, what might appear to be a close similarity is in reality an analogous route to the same compounds ( 1 4 ) . I n another example, three species of the genus Hymenoxys (Compositae), H . scuposa (DC.) K. F. Parker, H . acaulis (Pursh) K. F. Parker, and H . ivesianu (Greene) K. F. Parker, contain more than thirty flavonoids. The patterns of distribution of these compounds are correlated more strongly with population positions along an east-west gradient extending from Arizona to Texas than with the diagnostic morphological features of the species. The biochemical parallelism observed for populations of different species in the same region suggests the action of common selective forces (39). It has been observed that small, isolated island populations of mainland taxa usually have fewer and simpler compounds than their mainland ancestors. This may be because of lowered selection by predation or because island habitats have different environmental requirements (35).
14
DAVID S. SEIQLER
B. BASICPATHWAYS OF ALKALOID BIOSYNTHESIS

In the preceding section we have surveyed some of the ways in which variation originates and is maintained in plants. A knowledge of these variations is extremely important in systematic studies a t the lower taxonomic levels (genus-species), but when one wishes to establish relationships a t higher ranks, e.g., at the family, order, and subclass level, it is necessary to survey as many taxa and individuals as possible to reduce the effects of these variations. That is, we need to know what morphological features are produced and what biosynthetic pathways exist in a particular group of taxa to compare them. This is made more difficult by our imperfect knowledge of biosynthetic pathways, but, by careful observation of their products, we can establish certain relationships. I n this chapter we will mostly consider the application of alkaloids to systematic problems. Other secondary compound data can prove equally usable and should also be considered in a complete study of the relationship of systematics and secondary compounds. I have necessarily addressed those problems for which alkaloid data appear to be most helpful or promising and have not pursued certain relationships that may be more clearly established by other chemical and morphological data. I n this section I will survey some of the fundamental and widespread pathways of alkaloid biosynthesis. Studies of many of these compounds have proven useful a t lower taxonomic ranks but, due to the widespread appearance and presumably simple biosynthetic origin, are not as valuable for delineating the higher categorical levels, although in a few cases compounds that appear to be very simple are observed to have limited distributions. The simplest alkaloids are several amines derived from common amino acids such as phenylalanine, tyrosine, histidine, tryptophan, lysine, ornithine, and anthranilic acid. Alkaloids containing simple aromatic moieties and some of their simply derived relations have been reviewed (40-46). These simple amines arise by decarboxylation of the corresponding amino acids, often with subsequent methylation, hydroxylation, and addition of other groups. They are widely distributed, and their presence is usually not of taxonomic significance at the higher taxonomic ranks. These compounds are important because they are frequently beginning points for the synthesis of more complex alkaloids. Phenylalanine gives rise to phenylethylamine (6) and the correwhile tyrosine produces the corresponding methylated compound (7), sponding compounds tyramine (8) and N-methyltyrosine (9). I n the Gramineae tyramine is converted to hordenine (lo),which is widespread
1.
PLANT SYSTEMATICS
15
in 1 is family ,ut not restricted to it. Tyrosine is also converteL to two other important intermediate compounds, dihydroxyphenylalanine (DOPA) (11) and its cyclic derivative, cycloDOPA (12). These compounds are especially common as intermediates in the synthesis of alkaloids of the benzylisoquinoline and betalaine types as well as alkaloids widely distributed in the Cactaceae (47, 48) (see Section V, B). I n the Rutaceae many of these simple aromatic compounds are converted to the corresponding amides, such as fagaramide (13) from
10
11
12
13
Fagara xanthoxyloides Lam. Although most gymnosperms do not contain distinctive alkaloids (with the notable exception of the Taxaceae and Cephalotaxaceae), the genus Ephedra (Ephedraceae), a group only distantly related to more common gymnosperms, contains methylated phenylethylamines such as 1-ephedrine (14) and d-pseudoephedrine (15), which are also characteristic of this group of plants but not restricted to it (49-52).
CH3 HCNHCH,
CH3
I I
HC-NHCH, HO-C-H
8
14
HCOH
0
15
16
DAVID S. SEIGLER
The simple aliphatic compounds putrescine and cadaverine, derived from ornithine and lysine, respectively, are intermediates in the synthesis of many major groups of alkaloids and presumably occur in many plant groups but are seldom isolated and studied. Ornithine (or its successor N-methylputresine) gives rise to N-methylpyrrolidine via the reactions below (53).
CHa-NH,
CHaNHCH3
CHaNHCH3
I
CHa
CHa CHa CHNH, COaH
I I
+ CHS
COaH
I I CHNH, I
-con
CHa CH, CH,-NH,
__f
CHaNHCH3
A similar reaction series can produce the corresponding piperidine homolog from lysine. These compounds are easily alkylated by a number of compounds, for example, p-ketobutyric acid, to produce simple alkaloids such as hygrine (16) of the pyrrolidine type (43-55). I n a similar manner attack on an N-methylpiperidium cation yields
16
N-methylisopelletierine, an intermediate in the formation of characteristic alkaloids in the Punicaceae, Lythraceae, and Lycopodiaceae. Simple pyrrolidine and piperidine alkaloids are widespread among higher plants. Both groups may serve as substrates for additional alkylation reactions either internally to yield alkaloids such as tropine (17) and pseudopelletierine (18) or intermolecularly to yield more complex alkaloids. Pyrrolidine alkaloids are widespread, no doubt a reflection of the relatively small number of biosynthetic steps and chemical probability of their synthesis, but they are characteristically proliferated in a few families, such as the Solanaceae and Erythroxy-
1.
PLANT SYSTEMATICS
17
laceae and less commonly in others such as the Euphorbiaceae and Convolvulaceae and doubtfully in the Dioscoreaceae (49-52, 56, 57). Alkaloids of the piperidine type are more widely distributed. Many simply derived ones are found in the Crassulaceae, Punicaceae, and the Leguminosae, but they are also found in the Pinaceae, Euphorbiaceae, Chenopodiaceae, Equisetaceae, Piperaceae, Caricaceae, and Palmae.
17
18
Alkylation by phenylpyruvic acid may occur to produce other alkaloids characteristic of the Crassulaceae, such as sedamine (19) (53) and lobeline (20), found in the genus Lobelia of the Campanulaceae. Nicotinic acid may also alkylate the pyrrolidinium cation to produce compounds such as nicotine (21), one of the most widely distributed of all alkaloids (43, 50, 58). Many related compounds are found in the Solanaceae, especially in the genus Nicotiana. Anabasine (5) arises in Nicotiana by alkylation of the lysine-derived piperidinium cation. Coniine (22), the principal alkaloid of Conium (Umbelliferae), closely
20
22
18
DAVID S . SEIGLER
resembles intermediates in the synthesis of the isopelletierine alkaloids but has been demonstrated to be derived via a polyketide pathway (53, 59) from acetate precursors. This is a clear example of convergence in the types of compounds produced and it demonstrates why a knowledge of biosynthetic pathways is valuable in studies of phylogeny. Coniine has been reported from several other families (50).It would be especially interesting to determine the path of synthesis in each of these. Simple derivatives of tryptophan are also widely distributed in nature. Some, such as serotonin (23) and bufotenine (24), involve subsequent oxygenation. N,N-Dimethyltryptamine (25) and psilocybin (26) are widely known for their hallucinogenic properties. These compounds are more restricted in distribution than 23 and 24; 25 is
7H3
23
24
0-
HO-P=O
25
26
found in several families (50-52), but 26 appears t o be limited to fungi. Tryptamine and its derivatives serve as intermediates for many groups of alkaloids and by inference must occur in numerous plant taxa. Another group derived from tryptamine is the /?-carboline alkaloids,
Q - + . L O Z H ' N
H
--Q-,2&
N
H CH30 \ H
27
OTJ
/N
1.
PLANT SYSTEMATICS
19
which occur in many plant families such as the Passifloraceae, Symplocaceae, Zygophyllaceae, Eleagnaceae, Malphigiaceae, Euphorbiaceae, and Loganiaceae. Many families which contain alkaloids of the /3-carboline type are otherwise devoid of alkaloids. Histamine (28) is widespread in higher plants, but only a few alkaloids derived from the parent amino acid histidine, such as pilocarpine (29)) are known otherwise. Alkaloids of this type are mostly restricted to the Rutaceae (Casimiroa and Pilocarpus) and certain groups of fungi.
28
29
Dimerization of intermediate compounds from ornithine and subsequent cyclization can lead to the basic skeleton of the pyrrolizidine alkaloids (53). Further elaboration of basic pyrrolizidine structures
Ornithine + putrescino
H C O '
involves the type of oxidative process noted previously in relation to the biosynthesis of pyrrolidine and piperidine alkaloids. Pyrrolizidine alkaloids are usually esterified with mono or dibasic acids, many of which are unique to this series, e.g., heliosupine (30) and senecionine (31)(49-52, 60-64). Alkaloids of this type are found in several families
CH3 H3C'foH HO--CCHOH--CHB
I c=o I
30
31
20
DAVID S. SEIGLER
b u t are characteristic of the Boraginaceae (several genera), the Compositae (tribe Senecioneae), and the Leguminosae (Crotalaria)(49-52, 60-64). Similar reactions with cadaverine, derived from lysine, produce lupin alkaloids such as lupinine (3). I n this instance the corresponding aldehyde may condense with another molecule of piperidine t o yield sparteine (Z), and more complex compounds such as lamprobine (32), matrine (33). Alkaloids of this type are best known from certain genera of the Leguminosae (28, 49-52, 65).
32
33
I n this section several fundamental pathways of alkaloids biosynthesis have been examined. We will make frequent reference t o these in the subsequent examination of a number of specific taxonomic problems because all have been observed to occur in many higher taxonomic groups.
IV. Alkaloids in Lower Vascular Plants and Gymnosperms

Alkaloids are rarely found in lower plant groups. Algae, bryophytes, and ferns seldom contain compounds of this type. Among the lower vascular plants there are two notable exceptions; one is the genus Lycopodium, which contains complex alkaloids such as lycopodine (34) derived from lysine by means of precursors similar to those involved in the formation of pelletierine alkaloids in the Punicaceae (49-52, 66-69). The other exception is the genus Equisetum, which contains several alkaloids, such as palustrine (35). Nicotine (21) is also reported from Equisetum species. Although alkaloids are relatively uncommon among gymnosperms, simple compounds such as pinidine (36) are found in the Pinaceae and closely related families. The biosynthesis of compounds of this type has been previously outlined (Section 111, B). The Taxaceae (Taxales) (70) and Cephalotaxaceae (Cephalotaxales) (72, 72, 72a) contain alkaloids such as taxine (37), which is possibly
1.
PLANT SYSTEMATICS
21
34
of diterpine origin, and deoxyharringtonine (38),which are restricted to their respective families (and orders). The homoerythrina alkaloids of the Cephalotaxaceae are otherwise known only from the families Aquifoliaceae and Liliaceae (73, 7 4 ) . Both groups of alkaloids have antitumor activity and are extremely toxic.
nu
6H
31
OCH,
R = CH
CH-CHa-CH2C(OH)4H2COpMe CH3
38
3 - ~
I co;
The presence of complex alkaloids in the Taxaceae and Cephalotaxaceae supports the separation of these orders from other gymnosperms. This separation has been suggested by several workers on both paleobotanical and morphological grounds (75-77). Although the fungi represent a distinct evolutionary line and are
22
DAVID S . SEIGLER
probably as distant from plants as they are from animals in evolutionary terms ( I ) , they do possess several interesting types of alkaloids. Many ofthese compounds, such as psilocybin (26), which is found mostly in the genera Psilocybe and Stropharia, are derived from simple amines which are also widespread in higher plants. Muscarine (40) is a hallucinogenic choline analog found in the fly mushroom, Amanita muscaria. Others, such as gliotoxin (39) from Trichoderma viride, are more
CH,OH
39
40
complex in structure. Many nitrogen-containing compounds from Fungi imperfecti, especially the genera Penicillium, Streptomyces, and Aspergillus have pronounced antibiotic activity; these have been reviewed elsewhere (49, 50, 78-80). Indole alkaloids of the ergot type are found in Claviceps and also in t'he angiospermous plant family Convolvulaceae (Section V, B).
V. Alkaloids in the Angiosperms

A. INTRODUCTION Among the Angiosperms (flowering plants), Cronquist recognizes six subclasses of dicotyledonous and four subclasses of monocotyledonous plants ( 6 ) .Alkaloids are scarcely known from some of these, whereas in others they are common. Among the subclasses of Magnoliopsida (dicots)the Hamamelidae and Dilleniidae have few alkaloids-primarily simple bases and 8-carboline types that occur in many plant groups. Benzylisoquinoline alkaloids are characteristic of many orders of the subclasses Magnoliidae, although some tryptophan-derived bases are found in a small number of families which do not contain alkaloids of the benzylisoquinoline type. Diterpene alkaloids are found in several genera of the Ranunculaceae. The Caryophyllidae contain alkaloids derived from tyrosine and the corresponding dihydroxyphenylalanine (DOPA). Both simple types
23
and betalain pigments occur and their presence is characteristic of many families of the order. The situation is more complex in the subclass Rosidae, where families of some orders synthesize alkaloids and others do not. Those that produce significant numbers and types of alkaloids are the Rosales (Leguminosae and Crassulaceae), Myrtales (Lythraceae, Punicaceae), Proteales (Eleagnaceae), Cornales (Garryaceae, Alangiaceae), Euphorbiales (Buxaceae, Euphorbiaceae, Daphniphyllaceae, and Pandaceae), Celastrales (Celastraceae), Rhamnales (Rhamnaceae), Sapindales (Rutacae and Peganum of the Zygophyllaceae), Linales (Erythroxylaceae), and Umbellales (Conium of the Umbelliferae). There is little unity among the types of alkaloids produced by this group of plants. The extremely large and diverse family Leguminosae produces many types of alkaloids, among them are pyrrolizidine (Crotalaria), physostigmine (Physostigma), quinolizidine (several genera), Erythrina types (Erythrina),and Ormosia types (Ormosia). The Lythraceae produce an interesting type of quinolizidine alkaloids not known from other plants; the Punicaceae produce alkaloids similar to the better known tropane types; and the Garryaceae produce diterpene alkaloids, otherwise found principally in the Ranunculaceae. The Buxaceae contain alkaloids derived from triterpene skeletons. Euphorbiaceae is an extremely diverse family in terms of alkaloid types; in this regard, it is only rivalled by the Leguminosae and Rutaceae. Benzylisoquinoline, indole( ?), emetine( ? ), securinine, nicotine, polypeptide, Alchornea alkaloids, tropane, p-carboline, and simple bases are all known to occur within the family. The Daphniphyllaceae contain diterpene alkaloids of a unique type only known from this small family. The Pandaceae, Rhamnaceae, and Celastraceae contain alkaloids with attached polypeptide units. In the subclass Asteridae, many orders produce alkaloids. Among these are the Gentianales, Polemoniales (Solanaceae and Convolvulaceae), Lamiales (Boraginaceae), Campanulales (Campanulaceae), Rubiales (Rubiaceae), and Asterales (Compositae). The Gentianales and Rubiales are noted for prolific production of indole alkaloids and less for others of the tylophorine, monoterpene, and quinine type. The Solanaceae are known for the production of steroidal, tropane, and nicotine types, whereas a related family, the Convolvulaceae, produces both tropane and ergot alkaloids. The Boraginaceae and the tribe Senecioneae of the Compositae and Crotalaria, a genus of legumes, produce highly toxic alkaloids of the pyrrolizidine type. The genus Lobelia of the Campanulaceae synthesizes alkaloids of an unusual type restricted to that genus.
24
DAVID S. SEIGLER
B. THE MAGNOLIOPSIDA (DICOTYLEDONOUS PLANTS)

1. Introduction
The presence and phylogenetic significance of more advanced alkaloid groups in the various subclasses and orders of dicotyledonous plants (Magnoliopsida, sensu Cronquist) will now be examined. As the simple alkaloids previously discussed (Section 111, B) are of lesser significance from a systematic view, their presence will only be mentioned when appropriate, and numerous records of these compounds, which may be useful a t the lower categorical levels, will be omitted. The Caryophyllidae are probably the most primitive group and will be examined first, followed by the Magnoliidae and Rutaceae. The Hamamelidae, which do not contain alkaloids of complex structure, are omitted, as are all families of the Rosidae except for the few that contain alkaloids, i.e., the Leguminosae, Euphorbiaceae, Daphniphyllaceae, and Erythroxylaceae. Following this, a number of alkaloid types based on terpenoid structures will be examined. Most of these occur in families of the Asteridae, the most advanced subclass according to Cronquist, although some orders, such as the Cornales (sensu Cronquist), and a number of families of the Rosales possess the same iridoid compounds and certain of their alkaloidal derivatives. Members of the Nympheaceae (Magnoliidae, Sensu Cronquist) have sesquiterpene type alkaloids. The Garryaceae (Cornales, subclass Rosidae) and the genera Delphinum and Aconitum (Ranunculales, subclass Magnoliidae) as well as a few other isolated groups contain alkaloids based on a diterpene structure. The Apocynaceae (Holarrhena), the Buxaceae (Euphorbiales, subclass Rosidae), the Solanaceae, and many Liliaceous plants (of the Liliopsida) contain alkaloids based on steroidal and triterpenoid structures. Alkaloids based on tryptophan and monoterpene-iridoid structures and their distribution mostly in the families Apocynaceae, Loganiaceae, and Rubiaceae (all subclass Asteridae) will be reviewed. The relationship of alkaloid chemistry and systematics in several families of the Asteridae is then examined, e.g., the Solanaceae and the Convolvulaceae. The distribution of ergot alkaloids in the latter family and the fungal genus Claviceps is discussed.
2. The Caryophyllidae
The subclass Caryophyllidae is recognized by Cronquist as having

4 orders, 14 families, and about 11,000 species. Of these orders, the
Polygonales, Plumbaginales, and Batales are largely without alkaloids
1.
PLANT SYSTEMATICS
25
although harman, tetrahydroharman, and harmanine have been reported from a species of Calligonum of the Polygonaceae (50). I n contrast, alkaloids are widespread in most families of the Caryophyllales. They have been reported from the Aizoaceae (2500 species), Amaranthaceae (900 species), Basellaceae (20 species), Cactaceae (2000 species), Chenopodiaceae (1500 species), Didieraceae ( 9 species), Nyctaginaceae (300 species), Phytolaccaceae (150 species), and Portulaceae (500 species), but not from Caryophyllaceae (2000 species) and Molluginaceae (100 species). Because of the considerable controversy concerning the relationship of chemistry to the classification of this order, it has been studied more extensively than many others. Saponins are widely distributed through the order. They have been reported from the Aizoaceae, Molluginaceae, Amaranthaceae, Basellaceae, Cactaceae, Caryophyllaceae, Nyctaginaceae, and Phytolaccaceae. Many of these are based on triterpene aglycone skeletons (78, 81). Some species of the Chenopodiaceae contain a number of simple alkaloids derived from phenylalanine, tyrosine, tryptophane, ornithine, and lysine. Alkaloids derived from tyrosine are of particular interest because they are related to both benzylisoquinoline alkaloid precursors and precursors of the betalain pigments which are widespread in the order (37, 4 4 , 5 8 ) .Salsolin (41) is an example of an alkaloid of this type. Several relatively simple piperidine derivatives are found, as well as the
'
41
alkaloid anabasine (5), which in this instance is structurally but not biosyntheticalIy related to nicotine. Lupinine (3) and other quinolizidine alkaloids are found in Anabasis aphylla. Alkaloids with structures similar to those derived from tyrosine above are widely distributed in Caetaceae (43, 49-52, 78, 81). One of these, mescaline (42), is widely known for its hallucinogenic properties. Others such as anhalidine (43) and anhalonidine (44) show similarity to
OCH,
42
OH
43
44
26
DAVID S . SEIGLER
certain precursors of benzylisoquinolinealkaloids. Other, more complex, alkaloids involving mevalonate units such as lophocerine (45) and dimerization of simple alkaloid units occur.
45
The genus Mesembryanthemum and related genera of the Aizoaceae contain alkaloids such as mesembrine (46), which are also derived from tyrosine (82).
CH,
46
The most widespread alkaloids of the order, however, are betalain pigments derived from L-DOPA (83).These red or yellow compounds have ultraviolet absorptions in the same ranges as anthocyanins and probably serve much the same function in plants of the Caryophyllales. The occurrence of the two classes of compounds is mutually exclusive; no known plant in a betalain-containing family has ever been shown to contain anthocyanins and vice versa (26, 83-87). The families Caryophyllaceae and Molluginaceae contain anthocyanins, a fact that has been used to suggest that they should be segregated into a closelyrelated but distinct order (87). The red-violet pigment of beets is betanin (47) whereas the related yellow pigment from the cactus
HO
C0.H
47
48
27
SCHEME 1
Opuntia ficus-indica Mill. is indicaxanthin (48). The first of these compounds arises via Scheme 1. Once formed, betanin may be converted t o other compounds via routes similar to those shown in Scheme 2. Based on both chemical and morphological evidence, Mabry considers that the " Centrospermae families " (the Caryophyllales without the Caryophyllaceae and Molluginaceae) were derived from a common ancestral line from some precursor of the angiosperms and that this major
48
SCHEME 2
28
DAVID S. SEIOLER
evolutionary line gives rise to two lines, one anthocyanin containing, the other betalain containing (87').The early evolutionary divergence of the Caryophyllales and Polygonales from other angiospermous lines is supported by protein sequencing data of Boulter (88).The similarity of cytochrome c amino acid sequences suggests that the Polygonaceae (Polygonales) and the Caryophyllales are more closely related to each other than either is to other plants that have been sequenced. The postulated early origin of the Centrospermae is also in accord with studies based on both morphological and chemical features by other workers (78, 89-92) but does not agree with the origin of this group as postulated by Cronquist ( 6 ) ,who suggests that it is derived from the Magnoliidae. Both this data and benzylisoquinoline alkaloid data suggest that the Magnoliidae are not ancestral to the other subclasses of Angiosperms, with the exception of the Rutaceae and a few other families.
3. The Magnoliidae
The subclass Magnoliidae as defined by Cronquist consists of 6 orders, 36 families, and more than 11,000 species, and in his view, they are the most primitive of the angiosperms (flowering plants), evolutionarily speaking. The Aristolochiales and Papaverales have not been included with the other four orders by many workers [see Becker's comparison of taxonomic systems in Radford et al. ( 5 ) , p. 6171 but were included by both Takhtajan (69) and Cronquist ( 6 ) principally on the basis of morphological characters. Before discussing the alkaloids and systematics of this large group, it will be helpful to consider major morphological features that separate the orders of the subclass as well as their major chemical constituents. The Magnoliales are all woody plants that possess specialized cells that contain essential oils. These oils are primarily of terpenoid and phenylpropanoid origin. The nature of numerous chemical constituents of the Magnoliales as well as other orders of the Magnoliidae have been reviewed (78, 81). Several families have scarcely been examined, and
LslERiDAE
ROSlDLE
CARlOPHlLLlDlE
YAGNOLl IDLE
FIG.
1 . Subclasses of Magnoliopsida according to Cronquist (6).
1.
PLANT SYSTEMATICS
29
little can be said of the value of chemical characters for establishing their taxonomic position. Among these are the Amborellaceae (1 species), Austrobaileyaceae (2 species), Canellaceae ( 16-20 species), Degneriaceae ( 1 species), Schisandraceae (47 species), Trimeniaceae (7-1 5 species), and Winteraceae (95-120 species). When one compares the numbers of species in the remaining families, it is evident that a t least several species of the larger families have been examinedAnnonaceae (2100 species), Calycanthaceae ( 9 species), Eupomatiaceae (2 species), Hernandiaceae (50-65 species), Himantandraceae (2-3 species), Illiciaceae (42 species), Lauraceae (2000-2500 species), Magnoliaceae (215-230 species), and Monimiaceae (450 species). Members of the orders Piperales and Aristolochiales also have specialized oil cells, but in contrast to the Magnoliales are mostly herbaceous plants. The families of the small order Piperales, the Saururaceae (5-7 species), Piperaceae (1490-3000 species) (Cronquist accepts about 1500), and the Chloranthaceae (65-70 species) are generally low in alkaloid content but rich in compounds derived from phenylalanine or tyrosine metabolism via cinnamic acid and its relatives. The Aristolochiales, which consist of one family, the Aristolocbiaceae (600 species), are rich in compounds derived from the metabolism of cinnamic acid, p-coumaric acid, and their relatives but also contain many alkaloids. The Nympheales are aquatic plants that do not possess the oil glands typical of the three previously described orders. Some workers have considered the Nelumbonaceae to be sufficiently distinct so as to comprise a separate order, usually called the Nelumbonales ( 6 ) . Cronquist separates the Nelumbonaceae ( 2 species) from the Nympheaceae (65-93 species) (but retains both in his order Nympheales), largely on a basis of morphological characters, and the chemistry of these two groups has not been investigated with the exception of their alkaloids. The Ceratophyllaceae (4-1 0 species) has been little studied chemically. The Ranunculales also lack ethereal oil glands and most species of the order belong to three large families-the Ranunculaceae, Berberidaceae, and Menispermaceae. I n morphological features they are generally more advanced than the Magnoliales and are probably derived from them ( 6 ) . Chemical constituents from the three large families Ranunculaceae (800-2000 species), Berberidaceae (600-650 species), and Menispermaceae (350-425 species) have been studied extensively, but the remaining families of the order have been little examined. These are the
30
DAVID 5. SEIGLER
Circaeasteraceae ( 1 species), Lardizabalaceae (30-35 species), Coriariaceae (10-1 5 species), Corynocarpaceae (4 species), and Sabiaceae (90-1 60 species). The Papaverales consist of two families, the Papaveraceae and the Fumariaceae, which are advanced in many respects within the Magnoliidae. Cronquist considered the two families to be parallel groups that show different individual specializations a t least partly because of the absence of the latex system, which is well developed in the former family but missing in the later. These two medium-sized families have about 600 species ( 6 ) . Plants in these families excel in their ability to synthesize alkaloids of various types, but other constituents of the two families have not been examined to any great extent. Despite the widespread occurrence of compounds derived from phenylpropanoid metabolism and the almost ubiquitous presence of sizable quantities of terpenes within plants of the subclass, the presence of alkaloids derived from tyrosine and phenylalanine, namely those of the benzylisoquinoline type, more clearly defines the subclass. The general pathways leading to these benzylisoquinoline alkaloids have been reviewed (53, 93-98). This system arises from tyrosine (or phenylalanine?) in plants of the Magnoliidae by condensation of 3,4dihydroxyphenylethylamine and 3,4-dihydroxyphenylpyruvic acid and a subsequent Mannich condensation to yield norlaudanosoline (49) as the primary condensation product. This compound is subsequently methylated and desaturated to produce papaverine (50) in the opium poppy, Papaver somniferum (53, 93, 94). Methylation appears to occur after formation of the tetrahydrobenzylisoquinoline system but before dehydrogenation to papaverine. Norlaudanosine occurs with papaverine and also serves as an efficient precursor for its formation (53). Simple benzylisoquinoline alkaloids are known to occur in the Annonaceae, Hernandiaceae, Lauraceae, Magnoliaceae, Menispermaceae, Monimiaceae, Papaveraceae, Euphorbiaceae, Rhamnaceae, and Rutaceae (49-52). d-Reticuline (51), which is known to serve as an
HO
HO
HO
HO
49
CH30
60
CH30
51
31
intermediate in the biosynthesis of several more highly modified series of compounds is widely distributed and is known to occur in the Anonaceae, Hernandiaceae, Lauraceae, Monimiaceae, and Papaveraceae as well as the non-Magnoliidean family Rhamnaceae (49-52). Aporphine alkaloids [e.g., glaucine (53) and bulbocapnine (54)] have essentially the same distribution as simple benzylisoquinoline types (49-52) and arise by ortho-para coupling of compounds such as laudanosoline (52) (53, 94, 99-101) or where ortho-para coupling is not possible via the intermediacy of proaporphine compounds such as orientalinone (55) in the biosynthesis of isothebaine (56) in Papaver orientale L. (53,93,102). Aporphine alkaloids are known to occur in the
CH,O
CH,O
CH3
CH,O OCH,
53
HO
OH
51 54
cH30
HO
56
32
DAVID S . SEIGLER
Berberidaceae, Ranunculaceae, Fumariaceae, Aristolochiaceae, Magnoliaceae, Lauraceae, Hernandiaceae, Monimiaceae, Menispermaceae, Nelumbonaceae, Papaveraceae, Symplocaceae, Euphorbiaceae, Rutaceae, and the Rhamnaceae. Morphine alkaloids, such as morphine (57), also arise by ortho-para coupling of compounds such as 1-reticuline (58) in the family Papaveraeeae (53,93,94,103-108).Certain intermediates in this pathway occur in other families, for example, salutaridine (59) in Croton salutaris Casar of the Euphorbiaceae.
OH
58
57
I n Cryptocarya bowiei (Hook.) Druce, an Australian member of the family Lauraceae, benzylisoquinoline precursors yield compounds with closure to the isoquinoline nitrogen such as cryptaustoline (60) (53,109). In the family Papaveraceae, various species of the genera Argemone and Eschscholtzia synthesize alkaloids from benzylisoquinoline pre-
HO
60
0
59
33
cursors with another type of closure. Representatives of these are Z-eschscholtzine (61) and Z-munitagine (62) (53, 93, 94, 96, 110). I n the closely related Fumariaceae, closure occurs to include an oxygen atom ring of cularine (63) (48, 93, 94, 103).
?H
61
62
OCH,
63
The genus Cocculus of the Menispermaceae synthesizes alkaloids of the Erythrina type. Alkaloids of this type are known t o arise in the genus Erythrina (Leguminosae) by complex rearrangements of benzylisoquinoline alkaloids such as N-norprotosinomenine (53, 93, 94, 111115). The N-methyl carbon atom of several benzylisoquinoline alkaloids is known to participate in formation of a " berberine bridge " in compounds such as berberine (64)(116,117). Although protoberberine alkaloids are known to occur in several families (Anonaceae, Ranunculaceae?, Aristolochiaceae, Magnoliaceae, and Menispermaceae), they are characteristic of the genus Berberis (Berberidaceae) and of the genera Corydalis and Dicentra of the Fumariaceae (49-52). Stylopine (65)in the
34
DAVID S. SEIGLER
65
66
latter two genera is converted to protopine (66)(118).The benzophenanthridine skeleton encountered in a number of alkaloids of the Papaveraceae is also derived from benzylisoquinoline precursors (48, 93, 94). Chelidonine (67)is an example of this type of alkaloid. Phthalideisoquinoline alkaloids, e.g., narcotine (68), are also found in the Papaveraceae and Fumariaceae with occasional occurrences in the Berberidaceae and Ranunculaceae (49, 53, 93, 94, 119). Coupling of benzylisoquinoline units occurs in an intermolecular as well as in an intramolecular fashion (53,93,94,120,121). The individual components are usually linked by one or two diphenyl ether bridges.
<SO) (:%
OH
o
0
68
OCH,
OCH,
67
The distribution of compounds of this type is essentially the same as for the simple benzylisoquinoline units and aporphine alkaloids; they are found in the Menispermaceae, Lauraceae, Magnoliaceae, Monimiaceae, Hernandiaceae, Nelumbonaceae, Aristolochiaceae, and Ranunculaceae, with a questionable record from the Buxaceae (49-52). Aristolochic acid (69) occurs in the Aristolochiaceae and is often accompanied by aporphine alkaloids. Feeding studies have demonstrated that this naturally occurring nitro compound is probably derived from orientalinol (70) (94). Further, noradrenaline is incorporated into aristolochic acid with good incorporation rates, suggesting that 4-hydroxynorlaudanosoline is a precursor and that the 4-hydroxyl group is required for oxidation of the heterocyclic ring.
35
70
69
Many botanists agree that the orders of the Magnoliidae according to Cronquist are related and derived from common ancestors. This conclusion is largely based on morphological evidence, and chemical evidence i s considered supplemental, although in the subclass only the order Piperales and the order Nympheales (if one removes the Nelumbonaceae) lack either the simple benzylisoquinoline alkaloids or their more highly evolved derivatives. The Piperales are closely linked to other orders by the presence of many phenylpropanoid and terpenoid compounds as well as morphological features. The Nelumbonaceae are linked by the presence of benzylisoquinoline alkaloids to other orders of the subclass, but the other families of this order, especially the Nympheaceae, do not possess compounds of this type but rather alkaloids with a sesquiterpene skeleton. Because of the presence of ellagic acid and the absence of benzylisoquinoline alkaloids, Bate-Smith believes that the family Nymphaeaceae is completely out of place in this subclass (122),a view shared by some other workers (89-91). Pathways leading to benzylisoquinoline alkaloids are found in many (but not all) families of the remaining orders. Within these orders the presence of these types of alkaloids is observed because the plants that contain them descended from common ancestors and not because the pathways have evolved numerous times. The families Magnoliaceae, Annonaceae, Eupomatiaceae, Monimiaceae, Lauraceae, and Hernandiaceae of the Magnoliales contain benzylisoquinoline alkaloids. The families Himantandraceae, Myristicaceae, and Calycanthaceae contain alkaloids of other types, 71,26, and 72, respectively, and do not contain benzylisoquinoline alkaloids. At least one species of the Winteraceae contains alkaloids of an undetertermined type (123),whereas species of the Degeneraceae, Austrobaileyaceae, and Trimeniaceae have been tested and found not to contain alkaloids (78, 1234. The Lactoridaceae, Canellaceae, Illiciaceae, Schisandraceae, Amborrelaceae, and Gomortegaceae have apparently not been tested. The families Ranunculaceae, Berberidaceae, and
36
DAVID S . SEIQLER
Menispermaceae contain benzylisoquinoline alkaloids, while members of the Lardizabalaceae (123u, 123b), Corynocarpaceae (123a), and the have been tested and found not to contain Coriariaceae (123~-123c) alkaloids. The Sabiaceae and Circaeasteraceae have apparently not been tested. The families Aristolochiaceae (Aristolochiales)and the Papaveraceae and Fumariaceae (Papaverales) all contain benzylisoquinoline alkaloids as previously mentioned.
HC
8"
72
<N4&
71
Other lines of reasoning demand that certain families with other types of alkaloids [the Myristicaceae, Calycanthaceae (124), and Himantandraceae] must be accorded a place in the Magnoliales, but if so, what is their status! Have they lost the ability to synthesize benzylisoquinoline alkaloids and taken on the ability to synthesize others ? Or are they derived from non-benzylisoquinoline alkaloid synthesizing ancestors ? Similar questions may be asked about those families with no alkaloids, i.e., the Degeneriaceae and Trimeniaceae of the Magnoliales; the Lardizabalaceae, Coriariaceae, and Corynocarpaceae of the Ranunculales; the entire order Piperales; and the Nympheales exclu Nelumbonaceae. The complexity of structures derived from simple benzylisoquinoline skeleta is generally in accord with the origin of the orders as proposed by Cronquist. The simpler types of alkaloids are found in families of the Magnoliales and more highly derived compounds are found in the Aristolochiales on one hand and in families of the Ranunculales and Papaverales on the other (125). Certain genera and species within each of the above groups lack alkaloids. These should probably be interpreted as cases where mutations or metabolic changes have produced blocks to particular lines of biosynthesis. It is also possible that, for some unknown reason, other biosynthetic lines have been favored and the machinery needed to make
1.
PLANT SYSTEMATICS
37
benzylisoquinoline alkaloids sits unused. Examples of this are the genus Aniba of the Lauraceae, which appears to utilize the precursors that most Lauraceous plants convert into alkaloids to make compounds such as 6-styryl-2-pyrones, cinnamides, and neolignans; many species of the Piperaceae; certain species of Asarum of the Aristolochiaceae; and Podophyllum of the Berberidaceae (125). The distribution and taxonomic significance of benzylisoquinoline alkaloids within several families of the subclass have been reviewed. The distribution of alkaloids in the Lauraceae has been studied by Gottlieb (126). The family was subdivided into two subfamilies by Kostermans (127).I n the subfamily Lauroideae, the tribe Perseae seems capable of synthesizing only the most primitive types-those with the benzyltetrahydroisoquinoline skeleton. I n contrast, the tribe Cryptocaryeae can make numerous alkaloids, e.g., aporphines, 1-( w aminoethyl)phenanthrenes, benzylisoquinolines, bibenzpyrrocolin, and pavine types, as well as pleurospermine (73) and compounds similar to tylophorine (74). The other two tribes, the Cinnamomeae and Litseae, are in an intermediate position. The other subfamily, the Cossythoideae,
OCH, OCH,
73
74
consisting mainly of vines, is clearly different as it contains oxyaporphines and a morphine type alkaloid. The chemistry and distributions of phenylpropanoid derivatives, which seem to supplant the alkaloids in certain taxa, is discussed in detail in that work (125, 126). The treatment of Kostermans is largely upheld by data of alkaloid, phenylpropanoid, terpene, flavonoid, and other chemical origin. The distribution and systematic significance of alkaloids in the Menispermaceae has been recently reviewed (128).The alkaloids of this family are closely related to those of the Berberidaceae, Papaveraceae, Annonaceae, Rutaceae, and Ranunculaceae both in the type and range of alkaloids in agreement with Cronquists placement of this family. The family contains several unique types, such as the hasubanan skeleton (75) (which have the opposite configuration to that found in morphine
38
DAVID S. SEIGLER
types) and others of the Erythrina type such as dihydroerysodine (76) that are otherwise known only from the Leguminosae. I n contrast to the findings of Gottlieb in the Lauraceae, there is not such clear-cut correlation between the occurrence of specific alkaloid types and the subfamilies of the Menispermaceae [as proposed by Engler (129)],although the hasubanan, morphine, Erythrina, and novel bases are only found in tribes of the subfamily Menispermeae.
CH30 CH3
/ \
CH30
0
75
OH
76
There has been considerable debate in the past about the placement of the Papaverales in this subclass. This argument has largely been resolved by means of morphological characters, although the chemistry of this order closely resembles that of the Magnoliidae and especially the Ranunculales from which Cronquist supposes them to be derived (5-7). These alkaloids range from simple bases to some of the most complex structures derived from the benzylisoquinoline skeleton. Some of these (e.g., the protopines) are found in both the Papaveraceae and Fumariaceae, whereas other types are found only in the Fumariaceae (e.g., cularine, ochotensine, and sendaverine alkaloids) or only in the Papaveraceae (e.g., the papaverrubrin, pavine, isopavine, and benzophenanthridine types). Cronquist does not feel that the Papaveraceae and Fumariaceae are clearly distinct on purely morphological grounds, but the differences in chemistry strongly suggest that they are distinct a t the familial level (66, 81). Probably no other genus has been examined for the presence of alkaloids as extensively as Pupawer (Papaveraceae) (110); comprehensive reviews (108, 130, 131) have surveyed the results of alkaloid determinations in many species. Morphologically distinct seetions of the genus also have distinct alkaloid chemistry (110). In another genus, Argemone, subgeneric groupings are less distinct and chemistry does not clearly resolve them (110).This evidence does suggest that Argemone is derived from ancestors that had pavine-type alkaloids. The variation of alkaloids at the specific and subspecific or infra-
39
specific levels in plants of this group has been reviewed extensively because of their medicinal importance (14, 37, 78, 81, 107, 110). The effects of many environmental and genetic factors surveyed in Section I11 are reviewed by TBt6nyi (110).Within individual species quantities of alkaloids may be modified drastically by environmental factors but normally not the types produced. Many of these variations must be accounted for if one wishes to utilize alkaloid chemical data to study problems a t the specific or subspecific levels in the Papaveraceae.
4. The Rutaceae
The Rutaceae is one of the more interesting and complex families with regard t o alkaloid chemistry as well as the formation of flavonoids; mono-, sesqui-, and triterpenes; furocoumarins; and other secondary compounds (78, 81). The family contains alkaloids based on several major biosynthetic pathways, such as benzylisoquinoline (tyrosine), quinoline (132), furoquinoline (133),quinazoline (134), acridine (135) (anthranilic acid), imidazole (histidine),indoloquinazoline (tryptophan), and both simple aliphatic and aromatic amines (53, 93, 136-138). Quinoline and furoquinoline alkaloids are especially widespread within the family, being found in four of the five subfamilies from which alkaloids have been reported (136).Neither the furoquinoline, acridine, or indoloquinazoline alkaloids, which are derivatives of anthranilic acid, have been reported from sources other than this family (78, 81). Most reports of quinoline alkaloids are also from the Rutaceae. Benzylisoquinoline alkaloids occur widely in the Magnoliidae (Section V, B) and also in the Rhamnaceae, Euphorbiaceae, and Celastraceae. Engler (129) divided the Rutaceae into seven subfamilies-the Rutoidae, Dictyolomatoideae, Spathelioideae, Toddalioideae, Aurantioideae, Flindersioideae, and Rhabdodendroidae. Willis (139) felt that the groups that make up the Rutaceae differ to the extent that some could be regarded as independent families. Airy-Shaw (140)and Prance (141) recognized the Rhabdodendroideae as a close relative of the Phytolaccaceae; little, if any, chemical work has been done on this group. The Flindersioideae and Spathelioideae have been elevated to familial level and the former taxon placed in a position intermediate between the Rutaceae and the Zygophyllaceae (142), but recent evidence (137, 143, l 4 4 ) , largely based on alkaloid structures, suggests that both the Flindersioideae and the Spathelioideae should be maintained in the Rutaceae. Moore in Hegnauer (145) contended that the Rutoideae is a highly complex subfamily phylogenetically and that the present classification of the Rutaceae is one which runs directly
C<
40
q
0 OCH, CH3
DAVID 5. SEIOLER
OCH,
CH,O
* J
OCH,
Acronycine (an acridine alkaloid)
Skimmianine (a furoquinoline alkaloid)
Casimiroine (a quinoline alkaloid) CH,O
Qyq6
N
Arborine (a quinazoline alkaloid)
O r $
/
\
/
OCH3 5-Methoxyoanthin-6-one (a canthinone alkaloid)
Hortiacine (an indoloquinazoline alkaloid)
f
Pilocarpine (an imidazole alkaloid)
across the lines of specialization in floral anatomy." Waterman, in agreement with Moore's work, states that Engler's classification of both major subfamilies Rutoideae and Toddalioideae is untenable and proposes a new scheme of classification (137). Support for the view that the Rutaceae is a distinct and homogeneous group is provided by its essential oils and coumarins. Essential oils and coumarins are found in a t least four subfamilies. This view is also
41
confirmed by alkaloid chemical data: (a) furoquinoline alkaloids are essentially ubiquitous in the family and acridones are also widespread; (b) magnoflorine (77) and berberine (a), two of the most common alkaloids in the Ranunculales and the Magnoliales, occur in species of Rutaceae along with the chelerythrine (78), which is characteristic of the Papaveraceae.
CH,O
HO
OCH, CH,O 77 78
O Y O C H , OCH, 79 80
Alkaloids of the benzylisoquinoline type are mostly found in the genera Zanthoxylum (including Fagara), Phellodendron, and Toddalia. These three genera, which Engler placed in the Rutoideae-Zanthoxyleae, Toddalioideae-Phellodendrinae, and Toddalioideae-Toddaliinae,respectively, are closely related with an apparent phylogenetic link between Toddalia and Zanthoxylum (137). I n the Boronieae (Rutoideae), only furoquinolines are produced, whereas in the Diosmeae (Rutoideae) none are found. I n the Ruteae (Rutoideae)no less than five types of alkaloids are common to the three major genera. Alkaloids of the 1-benzyltetrahydroisoquinoline type are assumed to be primitive in the Rutaceae and thus the genera producing them are the most primitive extant genera of the family (78,89-91).As anthranilate-derived alkaloids are found in the same genera, it appears that the evolutionary trend was for direct replacement of one type with another (137). The genera of the Rutaceae that do not have l-benzyltetrahydroisoquinoline alkaloids, e.g., the Diosmeae, Boronieae (Rutoideae), and Aurantioideae, must be relatively advanced.
42
DAVID S . SEIQLER
The Rutaceae have been regarded by many as being especially close to the Zygophyllaceae, Cneoraceae, Meliaceae, Burseraceae, and Simaroubaceae ( l 4 5 ) ,and Cronquist considers the family to be a member of the order Sapindales, subclass Rosiidae ( 6 ) .No other families in this order contain significant quantities of alkaloids, essential oils, or coumarins, with the exception of the genus Peganum (Zygophyllaceae), which contains alkaloids of the harmine and quinazoline types, although these are not directly analogous to the alkaloids of the Rutaceae (78), Picrasma ailanthoides Planch (Simaroubaceae) which has been reported to contain 4,5-dimethoxycanthin-6-one (79), and Ailanthus giraldii Dode (Simaroubaceae) (3-dimethylallyl-2-quinolone)(80).The Rutaceae are chemically linked to the Meliaceae and the Simaroubaceae by a number of triterpenes and their derivatives. These compounds are derived from tirucallol(81) (or euphol, which has the opposite configuration a t C-20) and have highly oxidized skeletons that often render their recognition as triterpenes difficult (78, 94, 146).
81
The Burseraceae is known t o contain many essential oils rich in mono- and sesquiterpenes as well as triterpenes but does not contain the modified structures found in the preceding three families (78, 86). The Cneoraceae has not been studied chemically to any degree. The fact that the related families Simaroubaceae, Cneoraceae, and Meliaceae lack alkaloids suggests that they are relatively advanced with respect to the Rutaceae (137). This is partially confirmed by studies of the triterpenes of these families. Thus far, we have addressed ourselves to systematics within the family and to a discussion of what the close relations of the Rutaceae might be. Next we will examine several possibilities for the origin of the family. If our assumption that benzylisoquinoline alkaloids are primitive within the family is true, then we would anticipate (a) that the family is derived from ancestors that possessed benzylisoquinoline alkaloids, (b) that the pathways for these compounds evolved in some proto-Rutaceous species that were ancestral to other members of the group, or (c) that they evolved from ancestral species -that
43
possessed the necessary pathways to synthesize alkaloids but failed to express them and later in ancestral Rutaceous stock they became turned on once more. As previously mentioned, Cronquist (6)and other phylogenists (6, 69, 142, 147) generally place the family in the Sapindales or in similar groupings, such as the Rutales (sensu Taktajan). Few of the plants of these orders possess alkaloids of the appropriate type, nor do most members of the Rosales, hypothetical ancestors of the order. At this point we must either accept possibilities (b) or (c) above, or look for other possible ancestors. Several other workers (78, 89-91, 145) have postulated that the origins of the Rutaceae lie in the Magnoliidae, near the Ranunculales or Papaverales (145). While this appears unlikely to many it should be noted that this decision has been reached by several investigators (88, 148) on strictly morphological grounds.
5. The Leguminosae
The family Leguminosae, as defined by Cronquist, is a member of the Rosidae and one of the largest plant families with about 13,000 species. Takhtajan, Stebbins, and Hutchinson considered the group to be sufficiently distinct to comprise a separate order (12,69,142). The three subfamilies that make up the family, the Mimosoideae, Caesalpinoideae, and Lotoidae, have all been elevated to familial ranks by various authors. Most investigators have seen a fairly close relationship between the Leguminosae and Rosaceae. The family has many interesting secondary plant compounds, but none that characterize the family as a whole nor any that establish a close relationship to the Rosaceae. The alkaloids of this large plant family have recently been reviewed by Mears and Mabry (15). These compounds are widespread throughout the former but are largely missing from the latter family. Simple amines derived from phenyalanine, tyrosine, and tryptophan are widespread throughout the Leguminosae but are most commonly found in the subfamily Mimosoideae. Derivatives of the preceding amino acids occur in the genus Acacia and are also found as oxygenated and methylated derivatives, e.g., candicine (82), phenylethylamine, tyramine, and tryptamine in the genera Desmodium and Lespedeza. Physostigmine (83), a representative of an unusual type of alkaloid with great pharmacognostic value, is isolated from Physostigma venenosum Baifour, the Calabar Bean (15, 149, 150). Quinolizidine alkaloids are widespread in certain tribes of the subfamily Lotoideae, among which are the Genistae, Podalyrieae, and
44
DAVID S . SEIGLER 0
OH
8%
83
Sophorae. Although some of these alkaloids, such as lamprobine (32) and retamine (84), are restricted in distribution, the compounds lupinine (3), cytisine (85), and sparteine (2) are widespread in these tribes (15, 28). Cranmer and co-workers (20, 28) have presented arguments that the presence of lupine alkaloids in the Lotoideae suggests they originated from a common ancestral stock that contained a gene
84
85
pool for synthesizing these compounds. More complex derivatives of simple quinolizidine alkaloids have limited distributions in related genera. Matrine (33) and sophoramine (86)are only found in the genus Sophora and a few related genera. Related alkaloids, e.g., ormosamine
86
(87), are found in the genera Ormosia and Piptanthus. Although these genera have been placed in the tribes Sophoreae and Podalyrieae, respectively, the presence of complex pentacylic alkaloids suggests some relations (15). Pyrrolizidine alkaloids have a similar mode of origin to quinolizidine types, and it is not surprising that the genus Crotalaria (tribe Crotalinae), which is related to the quinolizidine-containing genera, synthesizes
1.
PLANT SYSTEMATICS
45
a7
these alkaloids. The Boraginaceae and the tribe Senecioneae of the Compositae also contain pyrrolizidine alkaloids. The biogenesis of Erythrina alkaloids has been reviewed (111-115). These alkaloids are derived from benzylisoquinoline alkaloids by complex rearrangements (53, 93, 94) and are known only to occur in the genus Erythrina and in certain genera of the Menispermaceae. The presence of sphaerocarpine (88) in Ammodendron has led Mears and Mabry (15)to suggest that this genus should be relocated with the
CH,O " O
CH,O
q
HO CH30
-CH,O
q
OH
HO
CH30
9-OH
46
DAVID S . SEIGLER
genera Genista and Adenocarpus, which have long been considered related and both produce similar alkaloids. Four of the 15-20 species of Erythrophleum have been reported to contain alkaloids such as cassamine (89), representing one of the rare reports of alkaloids from the Caesalpinoidae (151, 152).
88
89
The alkaloids of the three subfamilies are derived from distinct biosynthetic pathways with the exception of certain simple amines which are widely distributed but primarily found in the subfamily Mimosoideae. Thus, alkaloid chemical data (and other chemical data such as the distribution of canavanine and certain nonmetabolic amino acids) support the separation of these three groups. Alkaloid data is less informative with respect t o the identification of possible ancestors of any of the three subfamilies but it is interesting in this regard that ~r~thrin alkaloids a occur in the genus ~ r ~ ~ h r and i n aalso in certain members of the Menispermaceae and that many of the quinolizidine alkaloids found in the subfamily Lotoideae also occur in the Berberidaceae, Ranunculaceae, Papaveraceae, and Monimiaceae (all of the Magnoliidae) and only rarely in other sources (145, 153). Many of these records are in need of reexamination, as several of them are based on unvouchered plant materials and older chemical work. Further, the presence of numerous alkaloids derived from benzylisoquinoline pathways in the same plants suggests problems in identification of smaller amounts of cooccurring quinolizidine alkaloids. A few previous investigators (89-91) have considered the possibility that the Leguminosae are derived from a " ranunculalean-berberidalean " line on a basis of both chemical and morphological lines of evidence. Recent work by Boulter has shown that the amino acid sequence in cytochrome c from Phaseolus aureus Roxb. (Leguminosae, Lotoideae) and Nigella damascena L. (Ranunculaceae) are closely related (88). Alkaloid chemistry has been useful within the Leguminosae for the investigation of many problems a t the generic, specific, and infraspecific levels. Several of these have been reviewed by Mears and Mabry ( 1 5 , 2 2 ) .
47
6. The Euphorbiales
Cronquist ( 6 ) considers the family Euphorbiaceae (with about 7500 species) to be a member of the Euphorbiales, subclass Rosidae. The family is extraordinarily diverse in terms of both morphological and chemical characters and is of considerable economic importance. Qther workers have a t times placed the family in different orders. The Buxaceae (60 species), Daphniphyllaceae (35 species), and Aextoxicaceae (1 species), three other families of the order, were not considered closely allied to the Euphorbiaceae by Webster (154), while the Pandaceae (35 species) was thought to be related. Although the Euphorbiaceae contains many types of secondary plant compounds few of these are so widespread as to characterize the family. The principal exceptions are esters of phorbol(90) and other diterpenes which are found in genera belonging to several parts of the Euphorbiaceae as well as the Thymeliaceae [which Thorne places in his Euphorbiales, see Thorne (146)l (155-158). These compounds are apparently responsible for the irritating properties well known for members of this family.
90
R, = long, R, = short chain fatty acid
The alkaloids of the Euphorbiaceae have been reviewed by Hegnauer (153). Among these are compounds of the securinega type, such as securinine (91), which are widely distributed in two related genera, Securinega and Phyllanthus. It has recently been demonstrated that
91
48
DAVID 9. SEIQLER
these compounds are derived from L-tyrosine in a unique manner (159) in which tyrosine provides carbon atoms 6-13 of the securinine skeleton. The genera Hymenocaridia and Julocroton contain alkaloids, 92 and 93, respectively, that are based on polypeptide structures (153, 160). The genus Croton contains several benzylisoquinoline alkaloids, mostly of
NHC-CH(CH3)a
0
93
II
HN-H--CH(CH,), 0 NH-G-CH-N(CH3)S
II I
II I
0 CH(CH3)(Ca&)
92
the proaporphine type such as crotonsine (94). The genera Ricinus and Trewia contain two unusual alkaloids derived from nicotinic acid, ricinine (95) and nudiflorine (W), respectively. Alchorneine (97), alchorneinone (98), and other similar alkaloids have been isolated from AlchorneaJloribunda (161).These alkaloids appear to be of an imidazole
OCH,
I
HO
CH3
F
0
94
NcrJo
CH,
96
CH3
95
OMe
,OMe
97
1.
PLANT SYSTEMATICS
49
type. d-(3R, 6R )-3a-acetoxy-6/3-hydroxytropane, d-2a-benzoyloxy-3/3hydroxynortropane, and tropacocaine have been isolated from Peripentadenia mearsii (C. T. White) L. S. Smith (162). M,-Methyltetrahydroharman has recently been isolated from Spathiostemon javensis Blume ( =Homoroia riparia Lour.) and represents the first harman alkaloid from this family (163). A number of other alkaloid records in this family are questionable and should be reexamined. Among these are the presence of phyllalbine (a tropane type) in Phyllanthus discoideus Muell. Arg., 4-hydroxyhygrinic acid in Croton gabouga S. Moore, an ester of vasicine in Croton draco Schlecht., a bisbenzylisoquinoline alkaloid from Croton turumiquirensis Steyerm., yohimbine from Alchornea jloribunda Muell. Arg., and physostigmine from Hippomane mancinella L. [original references given in Hegnauer (153)]. Vouchering of plant materials is especially important in this group of plants, many of which are notoriously difficult to identify. Excluding these reports, the alkaloids of the Euphorbiaceae coincide reasonably well with the various subfamilial taxa although a large number of types are represented. Screening studies suggest that the Euphorbiaceae is still a source of unstudied alkaloids (123-123c, 1 6 3 ~ ) . The small family Pandaceae has recently been found to contain alkaloids such as 99, which closely resemble that of Hymenocaridia (Euphorbiaceae) and those of the Rhamnaceae (164) and Celastraceae (165).
99
The Daphniphyllaceae is a rather small family with 35-40 species, which most workers have considered to be related to the Euphorbiaceae (5, 6 ) . Webster (54),in accord with Hutchinson (142),would place the family in the Hamamelidae (sensu Cronquist). The chemistry of the family has been little studied with the exception of its unusual alkaloids. Some members of the family contain asperuloside, an iridoid monoterpene (Section V, B) ( 8 1 , 1 6 6 ) .Compounds of this type are not found in other families of the Euphorbiales (sensu Cronquist), nor are they
50
DAVID S. SEIGLER
commonly found in the Hamamelidae. They are, however, found in the Gentianales, Rubiales, Cornales, etc., which are discussed in Section V, B. The complex and unique alkaloids of this family, such as daphniphyllin (loo), have been shown to be of terpenoid origin. Six mevalonate units are involved in the synthesis of one alkaloid molecule (26, 167, 168).
100
Alkaloids which occur in the Buxaceae are derived from triterpenes and are discussed in Section V, B. I n summary, the Euphorbiaceae are rich in alkaloids of several major types. Two other families of the order that contain alkaloids, the Buxaceae and Daphniphyllaceae, do not appear to be closely related, while the third, the Pandaceae, produce alkaloids similar t o a t least one genus of the Euphorbiaceae. The Aextoxicaceae have apparently not been investigated. The ancestry of the Euphorbiaceae has long been in question. The family has been transferred from place to place although it has generally been considered close to the Geraniales or other orders of the Rosidae. Cronquist considers the Euphorbiales t o be descended from the Rosales (6), whereas Stebbins (12) did not consider the Rosales as necessary intermediates. The genus Croton contains benzylisoquinoline alkaloids. We should again ask the questions posed when we considered the origins of the Rutaceae: Did this family come from ancestors that synthesized benzylisoquinoline alkaloids, i.e., is it linearly descended from the Magnoliideae ; did benzylisoquinoline alkaloids arise independently in the family or did they come from a long line of intermediates in which synthesis of benzylisoquinoline alkaloids was turned off and in some proto-Euphorbiaceous ancestors was turned on again 2
7 . The Rhamnaceae and Celastraceae
The Rhamnaceae (Rhamnales) contain alkaloids of the benzylisoquinoline type as well as those with polypeptide skeletons; both of these types are found in the Euphorbiaceae. Cronquist ( 6 ) and other
51
workers have generally considered the orders Euphorbiales and Rhamnales to be somewhat related. Armepavine (101) has been isolated from Euonyrnus europaeus L. (Cefastraceae, order Celastrales) (165). Homoerythrina alkaloids, such as 102, have recently been reported from the genus Phelline of the Aquifoliaceae (73, 7 4 ) . Macrocyclic peptides have also been isolated from this species, further establishing the probability of close relationship between the Euphorbiales, Celastrales, and Rhamnales (165).
~ ~ ~ 0 2
CH30,
HO
CH3
CH,O
102
HO
/
101
Bhesa archboldiana (Merrill and Perry) Ding Hou has recently been reported to contain 9-angelylretronecine, its N-oxide, and calycanthine (169). The same questions as were asked about the ancestry of the Euphorbiaceae apply to the Rhamnaceae and Celastraceae.
8. Alkaloids in the Erythroxylaceae
Cronquist considers the Erythroxylaceae (Subclass Rosidae) to be related to the Linaceae, as have most other authors (6). The family is quite small (about 200 species), and many species contain alkaloids that are known for their physiological properties, such as cocaine (103), as well as other alkaloids derived from ornithine via pyrrolidine intermediates and from lysine (e.g. hygrine, pseudotropine, and anabasine). Neither of the two families (Linaceae or Humiriaceae) of the order Linales contain alkaloids, nor do plants of the Geraniales in which this family has also been placed. One must almost certainly conclude
,CH3
Nb
CO,CH,
H
OCOC,H,
103
52
DAVID S . SEIGLER
that the alkaloids of this family represent a case of independent evolution of tropane-type alkaloids.
9. Alkaloids with Monoterpene Sesquiterpene and Diterpene Skeletons
A number of monoterpenoid compounds, such as nepetalactone (104) of the iridoid group (49-53,93,94,170), incorporate nitrogen to produce alkaloids such as actinidine (105).These compounds are found in several plant families; among them are the Gentianaceae, Apocynaceae, Actinidiaceae, Bignoniaceae, Loganiaceae, Orobanchaceae, Menyanthaceae, Plantaginaceae, Oleaceae, Scrophulariaceae, Valerianaceae, and Dipsacaceae (49-52,lrOa).One of these compounds, gentianine, has been shown to be an artifact of isolation under certain conditions.
104
105
The parent terpenoids have wide distribution. They occur in ants of the genus Iridomyrmex and in many plants, primarily as the glycosides. Several aspects of the biosynthesis, distribution, and chemotaxonomy of this group of compounds have been reviewed ( 8 1 , 1 6 6 , 1 7 1 ) Many . of the families in which they occur are in the Asteridae and Rosidae (sensu Cronquist) and the presence of iridoid monoterpenes and the monoterpene alkaloids (Table I) appears to demonstrate several relationships within the group. For example, the presence of these compounds suggests a close relationship between the Actinidiaceae (order Theales) and the Pyrolaceae and Ericaceae (order Ericales), all of the subclass Dilleniidae. The presence of iridoid compounds in these three families is anomalous in the subclass. Investigations of plant taxa for the presence of both iridoids and the corresponding glycosides appears to be a fertile area to provide additional information for the placement of several families.
10. Alkaloids Derived from Tryptophan That Contain a Monoterpenoid Moiety
A large number of alkaloids that are important medicinally are derived by union of simple amines derived from tryptophan and an iridoid monoterpene unit. These are commonly known as the indole
TABLE I FAMILIES THAT
CONTAIN
53
IRIDOID COMPOUNDS As teridae Rubiaceae Scrophulariaceae Orobanchiaceae Globulariaceae Plantaginaceae Buddlejaceae Lentibulariaceae Apocynaceae Verbenaceae Martyniaceae Callitrichaceae Acanthaceae Dipsacaceae Pedaliaceae Labiatae Myoporaceae
Rosidae Escalloniaceae Daphniphyllaceae , Fouquieriaceae Cornaceae Garryaceae Hippuridaceae Hydrangeaceae (Hydrangea) Alangiaceae
Hamemelidae Eucommiaceae Hamamelidaceae (Liquidambar)
Dilleniidae Ac tinidaceae Ericaceae Proteaceae
alkaloids. The biosynthesis of simple amines derived from tryptophan and condensation of these units to produce Calycanthus alkaloids has previously been mentioned and the distribution of both iridoid monoterpenes and the corresponding monoterpene alkaloids has been summarized (Section V, B). Loganin (106), a precursor of most indole alkaloids, as well as of emetine alkaloids, is found in several families; among them are the
HO 0-glucosyl
CH30.C
106
CH3O.C
107
Apocynaceae, Loganiaceae, Meyanthaceae, and several Lonicera species (Caprifoliaceae) (171). The corresponding acid, loganic acid is found in the Gentianaceae, Apocynaceae, Alangiaceae, and Loganiaceae (119). Loganin is converted in certain plants to secologanin (107)) which is a more immediate precursor of indole and emetine alkaloids.
54
DAVID S. SEIOLER
Relatively unchanged addition products of tryptophan and secologanin u n i t s such as cordifoline (108) are found in Adina cordifolia Hook. of the Rubiaceae.
108
The corresponding decarboxylated compound strictosidine (109) has been found in Rhazya and Catharanthus species of the Apocynaceae, although the compound with opposite configuration a t C = 3 has not been isolated from the higher plants.
109
The route(s) from intermediates of the above type to the various types of indole alkaloids has been the subject of much speculation (171). Among the types observed are ajmalacine (110) and its relatives (Corynanthe type), stemmadinine types (lll),Aspidosperma types, such as tabersonine (112),Iboga types such as catharanthine (113),and Xtrychnos types such as strychnine (114). Several other basic skeletons are known, and the relation of many of these to the preceding types is enigmatic.
111
1.
PLANT SYSTEMATICS
55
112
113
114
Indole alkaloids are found in several families-the Nyssaceae, (Camptotheca acuminata Decne.), Icacinaceae, (Nappia foetidu Miers and Cassinopsis ilicifolia Kuntze), Alangiaceae, Loganiaceae, Apocynaceae, and Rubiaceae (49-52, 172-224). The families Nyssasaceae (8 species) and Alangiaceae (18 species) are members of subclass Rosidae order Cornales, whereas the families Icacinaceae (400 species) is a member of the order Celastrales. Other workers (225, 226) consider the Icacinaceae to be more closely related to the former two families. There is both chemical and morphological unity among the families Gentianaceae (1100 species), Menyanthaceae (40 species) (which Cronquist places in the order Polemoniales, subclass Asteridae), Loganiaceae (500 species), Apocynaceae (2000 species), Asclepiadaceae (2000 species), and Rubiaceae (6000-7000 species). All except the Asclepiadaceae contain precursors of the indole alkaloids if not the alkaloids themselves (e.g., the Gentianaceae and Menyanthaceae). The complex pathways leading to these compounds preclude independent evolutionary origin of the indole alkaloids they contain. The Apocynaceae has been divided into three subfamilies by Pinchon [see complete series of references in Hegnauer (78j.l Of these, the Plumerioideae contains indole alkaloids, the Cerberoideae monoterpene alkaloids, and the Echitoideae steroidal alkaloids (78).Problems a t the genus and species level have been extensively investigated in this family because of the medicinal importance of the alkaloids; several of these studies have been reviewed (18, 25, 145, 153, 186, 190-201, 204-212, 227, 228).
56
DAVID S . SEIGLER
The families Apocynaceae and Asclepiadaceae are closely related from a morphological view. Some authors have suggested that the two families intergrade and the line between the two is arbitrarily established ( 6 ) .Interestingly, alkaloid chemical data for the two families is distinct, although many of the intergrading taxa need to be examined. The family Apocynaceae is quite rich in indole alkaloids, whereas most species of the Asclepiadaceae are devoid of them, and the few that do contain alkaloids, mainly the woody genus Tylophora and members of the genus Cynanchum (or Vincetoxicum), contain compounds such as Z-tylophorine (115), which are derived from phenylalanine (and ornithine). Alkaloids of this type have also been reported from members of
OCHB
115
the Moraceae and Lauraceae (229-231), although some of these reports should be confirmed. Thus, the Asclepiadaceae appear to be a family that has either lost the ability to synthesize indole alkaloids or possibly is an example of a group with dormant pathways that may be reactivated a t some time in the future. The Loganiaceae has traditionally been segregated into six tribes; Hutchinson elevated these to five families in his Loganiales (142).Indole alkaloids are widespread in the tribes Gelsemiae and Strychneae; two of the other tribes have been little investigated. Another family, Buddlejaceae, has often been placed near or combined with the Loganiaceae; Cronquist places it in his Scrophulariales. Several species of the family contain alkaloids (123-123c, 163a), but no specific compounds have been characterized. Investigation of these alkaloids could provide useful information for the taxonomic placement of the family. The Rubiaceae (order Rubiales, subclass Asteridae) synthesize many indole alkaloids as well as compounds such as emetine (116), which are derived from similar pathways but with a dopamine instead of a tryptamine precursor and quinine (117) from extensive rearrangement
57
CH30,C
, A &
HN-'
116
117
of indole alkaloid precursors. The former (emetine type) are restricted t o the Rubiaceae and occur in several genera, among them Cephaelis and Psychotria. Quinine and closely related compounds are found in the genera Cinchona, Remija, Contarea, and Ladenbergia of the Rubiaceae. However, by far the most common alkaloids in the Rubiaceae are those that are identical with or derived from those found in the Apocynaceae and Loganiaceae. There is little question that the Rubiaceae must have been derived from common ancestors of the Gentianales or from members of the Gentianales. Did the families of the Asteridae that contain iridoid compounds and their derivatives come from families of the Rosidae that are iridoid containing (i.e., the Rosales) as Cronquist suggests? Or have these been derived from " Saxifragalean and Cornalean ancestors as other authors suggest (89-91) !' The same possibilities of independent origin, dormant biosynthetic mechanisms, or linear descent rise again.
)'
11. Alkaloids with Sesquiterpene Structures
Alkaloids with sesquiterpene skeletons are unusual in nature (49-52, 232,233) but are known to occur in the Nympheaceae (see the discussion of alkaloids in the Magnoliales). Both Nymphaea and Nuphar contain compounds such as 118 (26, 232, 233).
58
DAVID S. SEIQLER
118
The alkaloids of Nuphar and Xymphaea are not found in the Nelumbonaceae, nor are those of Nelumbo found in other families of the order. A clear dichotomy exists between the groups from both morphological and chemical grounds suggesting that the two groups are not closely related.
12. Alkaloids with Diterpene Structures
Alkaloids with modified diterpene structures occur in the Garryaceae (5 species)(order Cornales, subclass Rosidae), the genera Aconitum and Delphinum of the Ranunculaceae (order Ranunculales, subclass Magnoliidae), in Inula royleana DC. (order Asterales, subclass Asteridae), and Spiraea japonica L. (order Rosales, subclass Rosidae) (49-52, 78, 81). Many of these compounds are intensely poisonous and some are among the most toxic materials of plant origin known t o man. Several are used medicinally. These compounds may be divided into two broad categories. The first of these includes a series of relatively simple amino alcohols that are modeled on a C-20 skeleton, and the second group is more highly substituted and frequently based on a C-19 skeleton (234-239). These alkaloids arise from tetra- or pentacyclic diterpenes in which atoms 19 and 20 are linked with the nitrogen of a molecule of /3-aminoethanol, methylamine, or ethylamine t o form a heterocyclic ring (236).Pour basic skeletons of diterpene alkaloids are known. The veatchine skeleton, e.g., veatchine (119),which occurs in the genera Garrya (Garryaceae) and Aconitum (Ranunculaceae), is based on a kaurane skeleton (120) and obeys the isoprene rule. The other three skeletons, the atisine, lycoctonine, and heteratisine types,
19
1. PLANT S Y S T E M A l T C S
59
do not obey the isoprene rule and are found in both Aconitum and Delphinium species. Compounds such as atisine (121),Iyeoctinine (122), and heteratisine (123) are respective representatives of these groups. The latter two types are based on a C-19 skeleton. Alkaloids from Inula
120
121
OH
122 123
royleana (Compositae) are identical with certain alkaloids of the lycoctonine type which occur in the genus Aconitum ('78),whereas those from Spiraea (Rosaceae) (e.g., 124) represent a unique type. It is difficult to assess the taxonomic significance of these alkaloids. The kaurane series of diterpenes also give rise t o gibberellins, which are
OH
124
found in most if not all higher plants. The number of changes necessary t o produce compounds such as veatchine from these intermediates may be less than would appear on casual observation. No doubt many more changes are required to produce more complex diterpene alkaloid types. The Garryaceae are probably not closely related to the Ranunculaceae and neither are particularly close t o the Compositae.
60
DAVID S . SEIGLER
13. Alkaloids Containing Steroidal or Triterpenoid Nuclei
Several plant families produce alkaloids that are biosynthesized from steroids (240-249). The genera Holarrhena, Funtinnia, and Malonetia of the Apocynaceae and Sarcocca and Pachysandra of the Buxaceae produce alkaloids based on the 5-a-pregnane skeleton. Cholesterol has been suggested as an intermediate in the synthesis of steroidal alkaloids such as holophyllamine (125) and conessine (126) in species of Holarrhena (53).
CH,
125
126
The family Solanaceae is widely known for its diverse and plentiful alkaloid content. The genera Solanum and Lycopersicon (and others) contain steroidal alkaloids that are similar in structure t o the steroidal saponins they possess. Many of these compounds have complex. di- and trisaccharide moieties. Alkaloids of this type, such as solanidine (127) and solanocapsine (128), indicate a close relationship between these alkaloids and cholesterol.
' r
H O '
H
127 128
The structures of several C-nor-D-homosteroids from the genus Veratrum of the Liliaceae will be discussed in Section V, C. Several members of the Buxaceae (Euphorbiales sensu Cronquist) contain exceedingly complex mixtures of alkaloids (250).Most of these alkaloids have substitution patterns that resemble triterpenes but do not possess the typical C- 17 side chain. Several possess cyclopropane rings reminiscent of cycloartenol, such as cyclobuxine-D (129), whereas others, such as buxenine-G (130), have a ring expanded system.
61
129
130
Buxus alkaloids are not known from other plant groups, although they are widespread in the family. Webster (154) does not feel that the Buxaceae is closely related to the Euphorbiaceae; the two families have few chemical characters in common (78). Hutchinson (142) suggested the family was in the Hamamelidales, but there is little chemical evidence to confirm or deny this placement.
14. The Solanaceae
The Solanaceae is one of the richest families with regard to the absolute number of species that contain alkaloids. Cronquist places the Solanaceae in the order Polemoniales of the Asteridae ( 6 ) .It is the largest family in the order with about 2300 species (about 1700 of these in the genus Solanum) followed by the Convolvulaceae with about 1400. While the Solanaceae are extremely rich in alkaloids, few are found in other families of the order. Pyrrolidine and tropine types have been reported from the genus Convolvulus and ergot alkaloids (Section v, B) are present in the Convolvulaceae (49-52, 5 6 5 5 ) . A large number of genera of the Solanaceae contain alkaloids derived from ornithine via pyrrolizidine intermediates (Table 11) (53, 93, 94). The biosynthesis of these alkaloids has been previously discussed
TABLE I1
GENERAOF
THE
SOLANACEAE THAT CONTAIN ALKALOIDS DERIVED FROM ORNITHINE AND LYSINE

Solanum Solandra Physalis Anisodus Nieandra Methysticodendron Withania Nicotiana Brugmansia Salpiglossis Salpichroa Streptosolen Dunalia Cyphomandra Anthoeereis
Atropa Hyoscyamw Physochlaina Datura Duboisia Latura Mandragora Scopolia
62
DAVID S . SEIGLER
(Section 111, B). These plants are distributed in all five subfamilies of the family as seen by Wettstein (78).Nicotine and anabasine are found in several genera that contain other ornithine- and lysine-derived compounds (e.g., Duboisia, Nicotiana, Withania, and Salpiglossis). The distribution of certain steroidal glycosides with skeletons such as 131 below has been reviewed by Lavie (251). This group of chemists studied the complex inheritance patterns of these compounds in several genera- Withania, Physalis, Jaborosa, Nicandra, and Acnistus.
'.
Steroidal alkaloids of these and other types are widely distributed through the family (Table 111) and parallel the presence of steroidal glycosides in the family. The genus Solanum is noted for the types of both steroidal glycosides and alkaloids that it contains. Similar compounds are also found in the genus Veratrum of the Liliaceae (Section
v, C).
15. Ergot Alkaloids
This group of indole alkaloids is found in members of the fungal genus Claviceps, especially Claviceps purpurea (Fries) Tul. (an obligate parasite of rye), and in certain members of the angiospermous family Convolvulaceae (49-52, 78, 81). Compounds of this type, e.g., agroTABLE I11
GENERA OF THE SOLANACEAE THAT CONTAIN STEROIDAL ALKALOIDS Lycopersicon Solanum Cestrum Cyphomandra Capsicum Physochlaina Scopolia Withania
1.
PLANT SYSTEMATICS
63
132
clavine (132),arise by condensation of tryptophan and mevalonate units Alkaloids and subsequent cyclization (27,53,93,94,216,220,221,252). of the clavine series are found in both Claviceps and in the genera Rivea and Ipomoea of the Convolvulaceae. In certain alkaloid-producing strains of ergot, agroclavine (132) is converted to elymocIavine (133), which serves as a precursor for lysergic acid (134) and other related
132
133
compounds. Ergine (lysergic acid amide) (135) and erginine (isolysergic acid amide (136) have been isolated from hydrolyzates of Rivea corymbosa (L.)Hall. f. and Ipomoea tricolor Cav., which were used by Mexican indians as a drug under the name ololiuqui (221, 253). The majority of alkaloids from ergot are peptides of lysergic acid. The therapeutically most important ergot alkaloids are of this type. There is no question of close relationship between Claviceps (an Ascomycete) and the Convolvulaceae (an angiosperm from an evolutionarily
134
135
136
64
DAVID S . SEIGLER
advanced family). The pathways leading to both clavine and lysergic acid types appear to be identical in both groups, precluding origin by different pathways or at best making it very unlikely. Alkaloids of the complexity of ergot types are seldom encountered among fungi (78) and are otherwise unknown from the Convolvulaceae (49-52, 78, 81). Did these pathways evolve independently and against statistical odds in the two groups! Another possibility is suggested by Went ( 3 6 ) in his discussion of parallel (convergent 1 ) evolution in which he discusses the possibility that genetic units have been transferred from organism to organism by the action of viruses or other parasitic forms of life. It is known that viruses are capable of transferring genetic material between certain strains or species of bacteria ( I ) , but this process has not been established for more highly evolved organisms. Although most of Wents examples can be more easily explained by other mechanisms (such as natural selection acting upon a highly variable gene pool) one cannot discount the possibility of such transfers in cases such as ergot alkaloid synthesis.
16. Miscellaneous Alkaloids and Families
a. Tylophorine and Related Types of Alkaloids. Alkaloids of this general type have been isolated from the Asclepiadaceae (Tylophoraand Cynanchum or Vincetoxicum),the Lauraceae (Cryptocarya), the Urticaceae (Boehmeria platyphylba and B. cylindrica) (254, 254a), and the Moraceae (Ficus). Tylophorine (115) alkaloids in the Asclepiadaceae have been suggested t o arise from condensation of a phenylalanine and an ornithine unit and subsequent union of a unit of tyrosine (2543).The biosynthesis of cryptospermine (74) type alkaloids has not been investigated. It is generally conceded that the Moraceae and Urticaceae are closely related, but the other two families are quite distant. b , The Elaeocarpaceae. The family Elaecarpaceae contains a unique type of alkaloid such as d-isoelaeocarpicine (137)(255).Alkaloids are otherwise rarely reported in the Malvales. C . The Cruciferae. Several nitrogen-containing compounds have been
H
137
65
isolated from this family, most of which are related to the glucosinolates which are widespread in the family, although several (e.g., 138),mainly those from the genus Lunaria appear to be of a unique type (78,81,256).
138
C. THE LILIOPSIDA (MONOCOTYLEDONOUS PLANTS)

Alkaloids among the monocotyledonous plants are, with the exception of simple amines, mostly found in families of the Liliales and the Orchidales, although a few are known to occur in other families. Liriodenine, lysicanine (139), and nuciferine have been reported
CH,O
139
from Lysichitum camtschatcense Schott. var. japonicum Makino of the Araceae (order Arales, subclass Arecidae) (257).Several simple alkaloids, such as arecoline (140), are found in the Palmae (order Arecales, subclass Arecidae). A number of simple amines, e.g., hordenine (12), candicine, tyramine, and N-methyltyramine, are widely distributed in the Gramineae (49). More complex alkaloids such as festucine (142) and loline (143), pyrrolizidine alkaloids that occur free in nature, have been
CH,
140 141
66
DAVID S. SEIGLER
HNCH,
142
143
found in the genera Festuca and Lolium, respectively. Perlolyrine (144) has also been isolated from the genus Lolium (258). Most alkaloids of the monocotyledonous plants are concentrated in the Liliidae, especially in the order Liliales, but also in the Orchidales.
CH,OH
144
Alkaloids commonly found in the Liliaceae (including the Amaryllidaceae) are derived from phenylalanine and/or tyrosine but differ in structure from types found in dicotyledonous plants. Alkaloids in the Orchidaceae are mostly restricted t o several genera of that family and are of an unusual type.
1. The Liliales
The Liliales, as defined by Cronquist, comprise 13 families and nearly 7700 species. He combines the Liliaceae and Amaryllidaceae to produce the largest family of the order, the Liliaceae, which has about 4200 species. Other families in the order are the Iridaceae (1500 species), Dioscoreaceae (650 species), Agavaceae (550 species), Smilacaceae (300 species), Velloziaceae (200 species), Haemodoraceae (1 20 species), Xanthorrhoeaceae (50 species), Pontederiaceae (30 species), Stemonaceae (30 species), Taccaceae (30 species), Philydraceae ( 5 species), and Cyanastraceae (5 species). Of these, alkaloids are known from the Liliaceae (from members of both the former Liliaceae and Amaryllidaceae), Dioscoreaceae, and Stemonaceae (49-52). The Liliaceae and Amaryllidaceae were traditionally separated from one another by the single character of position of the ovary-inferior in Amaryllidaceae and superior in the Liliaceae ( 6 ) . This difference is now not considered so significant with separation of the Agavaceae from this group, and Cronquist says that it appears the traditional
1.
PLANT SYSTEMATICS
67
COMMELINIDAE
FIG.2. Subclasses of Liliopsida according to Cronquist (6).
Amaryllidaceae were really several different groups that had independently become epigynous. Steroidal glycosides are widespread among species of the Liliaceae, Agavaceae, and Dioscoreaceae, but are not found in the Amaryllidaceae (78, 81). The Amaryllidaceae alkaloids comprise a unique group of bases that have so far been found only in that family (49-52,259-261). Conversely, with the exception of hordenine, alkaloids of other plant families have not been found in the Amaryllidaceae. Three major pathways of alkaloid biosynthesis in this family arise from the compound norbelladine (145), which is derived from one molecule of tyrosine and one molecule of phenylalanine. One of these pathways gives rise to lycorine
HO+&H,NHCH.
145
dOH
(146) and its congeners via Scheme 3. A second gives rise to haemanthamine (147), pretazettine (148), and tazettine (149) via Scheme 4. The third pathway gives rise to compounds such as narwedine (150) and galanthamine (151) via Scheme 5. All three pathways are present in many genera of the family (49-52, 7 4 , 78, 81) and in most of the tribes of the Amaryllidaceae according to Hutchinson (78).Other subfamilies, a number of which were raised to the rank of family by Hutchinson, do not have these alkaloids (142). In some members of the Liliaceae, one molecule of phenylalanine and one molecule of tyrosine unite to form series of compounds such as colchicine (152) and androcymbine (153).
68
DAVID 5 . SEIGLER
Norbelladine --+
CH30
OH
CH.0
++
HO
146
SCHEME 3
147
HO
148
149
SCHEME 4
150
CH,O
.*-
151
SCHEME 5
69
OCH,
CH,O
Hutchinson (142)divided the Liliaceae into 28 tribes and a t the same time elevated a number of groups previously placed in the Liliaceae to familial level (78).Of these 28 tribes, the Uvularieae, Anguillarieae, and Colchiceae contain colchicine and related alkaloids. These alkaloids are present in the genera Androcymbium, Colchicum, Gloriosa, Littorica, Merendera, Camptorrhiza, Kreysigia, Dipidax, and Iphigenia but absent from many others from which related alkaloids have been reported (262-265). The Veratreae, a related tribe, contain many alkaloids that are derived from steroidal precursors such as cholestanol as well as those of the C-nor-D-homo type (78,247-250). These extremely toxic compounds are found throughout the genera Veratrum, Schoenocaulon, and Zygadenus and are similar to those found in the Solanaceae, Buxaceae, and Apocynaceae. An example of the former type is veralkamine (154).
H
154
The genus Fritillaria of the subfamily Lilioideae contains alkaloids that are similar in structure to those of the Veratreae. The similarity in alkaloids and in certain lactones leads Hegnauer (78) to suggest a relationship between the two groups. Others have previously considered the Lilioideae to be derived from members of the Melanthioideae (265). The Dioscoreaceae is best known for the steroid glycosides its species contain. These are similar in structure to those found in the Liliaceae, Agavaceae, and certain allied groups. I n contrast to the Liliaceae, however, the Dioscoreaceae contain alkaloids based on a quinuclidine structure such as 155 (49-52, 78). It has now been demonstrated that four acetate units are condensed with a lysine derived piperidine unit to
70
DAVID S. SEIGLER
yield Dioscorea alkaloids (266).To date these have only been found in African and Asian species of the genus, and interestingly, those with alkaloids were found to be practically free of saponins (78). Earlier reports of tropane alkaloids in this family are probably erroneous.
155
The Stemonaceae, a small family of three genera (4,have been shown to contain approximately fourteen alkaloids of a unique type such as tuberostemonine (156).
156
Cronquist views the families of the Liliales as being derived from the Liliaceae, with the exception of the Philydraceae and Pontederiaceae. He further views the Amaryllidaceae as several groups of the Liliaceae that had independently become epigynous. The Dioscoreaceae and Stemonaceae are broadleaf climbers that are also derived from Liliaceous parents. The Iridaceae are much like the Liliaceae in that they frequently exploit the bulbous and cormose habit, but they have not been reported to contain alkaloids. I n summary, alkaloid chemistry suggests that the Liliaceae and several groups of the Amaryllidaceae are distinct. The Dioscoreaceae and Stemonaceae contain alkaloids not found in either and do not contain alkaloids of the type found in the Liliaceae-Amaryllidaceae.
2. The Orchidaceae
This large family with approximately 20,000 species has been little investigated chemically but is known to contain alkaloids derived from ornithine. Appropriate alkylation of a pyrrolidine intermediate with an acetate- andfor propionate-derived precursor gives compounds such
71
as crepidine (157), which are known principally from the genus Dendrobium but also from other genera which have been summarized (78, 81, 267-269). Simpler compounds such as hygrine (16) have also been
157
reported from several genera and add credence to the proposed biosynthesis of more complex alkaloids by the internal alkylation of a pyrrolidine moiety. Pyrrolizidine types such as 158 from the genus Lipuris and Mu&xis are also known.
R '
various R and R' substituents
158
The differences between major groups of orchids have few absolute distinctions and several taxonomic schemes have been proposed, for example, those by Garay (270), Dressler and Dodson (271), and Airy-Shaw (140).Most alkaloid-containing species are concentrated in the group Epidendreae and especially in the genus Dendrobium. Cronquist views the Orchidaceae as being derived from the Liliales, probably from Amaryllidaceous ancestors. The alkaloids of this giant family do not resemble those of the Lilales, nor do the Orchidaceae contain alkaloids of the types found in either the Amaryllidaceae, the Liliaceae, or other extant families of the Liliales.
3. Alkaloid Chemical Data and the Origin of the Monocotyledonous
Plants Bessey (272) and several other systematists proposed that the monocotyledonous plants arose from plants similar to the Ranunculales and that primitive monocots resembled the Alismatales. Cronquist ( 6 )
72
DAVID S. SEIGLER
discards this theory and derives them from the Nympheales of his Magnoliidae, primarily on a basis of resemblance of extant members of the Nympheales (especially Nymphuea and Nuphur), to a model he proposes for a primitive monocotyledonous plant. Stebbins (12) rejected this hypothesis as well as that of Bessey, as he felt many of the characters used by both of the previous investigators were secondarily derived rather than primitive. He further states that no modern orders of either monocotyledonous or dicotyledonous plants are derived from extant ancestors and suggests that monocots are derived from ancestors similar to Drirnys (Winteraceae, subclass Magnoliidae). Chemical data do not clearly resolve problems related to the origin of monocots. Alkaloids of the monocots are different from those of the dicots. I n only a few cases similar compounds are produced, e.g., some amaryllidaceous alkaloids resemble those derived from benzylisoquinoline precursors, certain orchidaceous alkaloids resemble those derived from ornithine in dicots, and steroidal alkaloids of the Liliaceae resemble those of the Solanaceae, Apocynaceae, and Buxaceae. Several simple amines (tyramine, gramine, tryptamine, candicine, etc.) do occur in monocots and dicots, but as previously discussed these are rarely significant a t higher taxonomic ranks. If the proposals of either Bessey or Cronquist are correct it is necessary to derive the monocots from non-alkaloid-containing lines or to suppose that the ability to synthesize either benzylisoquinoline alkaloids of advanced types (as occur in the Ranunculales) or sesquiterpene alkaloids (as occur in the Nympheales) has been lost. From extant data for the distribution of alkaloids in monocots it is clear that most primitive monocots (as discerned by either the system of Bessey or Cronquist) are devoid of alkaloids, and alkaloid synthesis as seen in monocots, e.g., the Liliales, must be independently derived. Cronquist suggests that the Winteraceae is one of the families ancestral to other families of the order Magnoliales. It is interesting that no benzylisoquinoline alkaloids have been isolated and characterized from this family. On the other hand, benzylisoquinoline alkaloids have been reported from a t least one monocot, a member of the Arales (257), although with apparently unvouchered plant materials. This record should be reexamined since it represents a most important occurrence for studies of phylogeny and origin of this group. Studies of the amino acid sequences of cytochrome c by Boulter (88) indicate that monophyletic origin of the monocots from dicotyledonous lines is probable. It also appears from this evidence that both the monocotyledonous and magnolidean lines diverged after those of the Caryophyllales and thus the flower and chemistry of truly primitive angiospermous plant may resemble that proposed by Meeuse (89-91) rather than the Ranalean type, which has become widely accepted.
1.
PLANT SYSTEMATICS
73
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202. A. I. Scott, P. B. Reichardt, M. 13. Slaytor, and J. G. Sweeney, Recent Adv. Phytochem. 6, p. 117 (1973). 203. G. F. Smith, i n The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 592. Academic Press, New York, 1965. 204. V. Snieckus, in The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 1. Academic Press, New York, 1968. 205. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 250. Academic Press, New York, 1965. 206. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 203. Academic Press, New York, 1965. 207. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 789. Academic Press, New York, 1965. 208. W. I. Taylor, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 79. Academic Press, New York, 1968. 209. W. I. Taylor, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 99. Academic Press, New York, 1968. 210. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 125. Academic Press, New York, 1968. 211. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 272. Academic Press, New York, 1965. 212. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 41. Academic Press, New York, 1968. 213. W. Solomon, in Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 301. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 214. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 238. Academic Press, New York, 1965. 215. W. I. Taylor, in The Alkaloids (R. H. F. Manske, ed.), Vol. XI, p. 73. Academic Press, New York, 1968. 216. R. Thomas and R. A. Bassett, Prog. Phytochem. 3, 47 (1972). 217. R. H. F. Manske, in The Alkaloids (R. H. F. Manske, ed.), Vol. VII, p. 419. Academic Press, New York, 1960. 218. M. Janot, i n The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. 111, p. 363. Academic Press, New York, 1953. 219. H. T. Openshaw, in Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 85. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 220. A. Stoll and A. Hofmann, in The Alkaloids (R. H. F. Manske, ed.), Vol. VIII, p. 726. Academic Press, New York, 1965. 221. A. Stoll and A. Hofmann, i~ Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 267. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 222. R. B. Turner and R. B. Woodward, i n The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. 1 1 1 ,p. 1. Academic Press, New York, 1953. 223. M. R. Uskokovic and G. Grethe, in The Alkaloids (R. H. F. Manske, cd.), Vol. XIV, p. 181. Academic Press, New York, 1973. 224. T. R. Govindachari, i n The Alkaloids (R. H. F. Manske, ed.), Vol. I X , p. 517. Academic Press, New York, 1967. 225. E. C. Bate-Smith, I. K. Ferguson, K. Hutson, S. R. Jensen, B. J. Nielson, and T. Swain, Biochern. Sya-t. Ecol. 3 , 79 (1975). 226. R. H. Dahlgren, Angiospermernes Taxonomi. Akad. Vorlag, Copenhagen, 1974. 227. G. H. Aynilian, N. R. Farnsworth, and J. TrojBnek, in Chemistry in Botanical Classification (G. Bendz and J. Santesson, eds.), p. 189. Academic Press, New York, 1974.
1.
PLANT SYSTEMATICS
81
228. W. I. Taylor and N. R. Farnsworth, The Vinca Alkaloids. Dekker, New York, 1973. 229. J. H. Russel, N a t u k s . 12, 443 (1963). 230. E. Gellert and N. V. Riggs, Aust. J . Chem. 7 , 113 (1954). 231. E. Gellert, A w t . J . Chem. 9, 489 (1956). 232. J. T. Wrobel, i n The Alkaloids (R. H. F. Manske, ed.), Vol. I X , p. 441. Academic Press, New York, 1967. 233. 0. E . Edwards, in Cyclopentanoid Terpene Derivatives (W. I. Taylor and A. R. Battersby, eds.), p. 357. Dekker, New York, 1969. 234. S. W. Pelletier and L. H. Keith, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XII, p. 136. Academic Press, New York, 1970. 235. S. W. Pelletier and L. H. Keith, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XII, p. 2. Academic Press, New York, 1970. 236. S. W. Pelletier and L. H. Keith, i n Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 503. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 237. E. S. Stern, i n The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. IV, p. 275. Academic Press, New York, 1954. 238. L. H. Keith and S. W. Pelletier, i n Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 549. Academic Press, New York, 1970. 239. E. S. Stern, i n The Alkaloids (R. H. F. Manske, ed.), Vol. VII, p. 473. Academic Press, New York, 1960. 240. V. Prelog and 0. Jeger, in The Alkaloids (R. H. F. Manske, ed.), Vol. VII, p. 343. Academic Press, New York, 1960. 241. Y. Sato, i n Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 591. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 242. K. Schreiber, i n The Alkaloids (R. H. F. Manske, ed.), Vol. X, p. 1. Academic Press, New York, 1967. 243. 0. Jeger and V. Prelog, i n The Alkaloids (R. H. F. Manske, ed.), Vol. VII, p. 319. Academic Press, New York, 1960. 244. V. Cerny and F. Sorm, i n The Alkaloids (R. H. F. Manske, ed.), Vol. I X , p. 305. Academic Press, New York, 1967. 245. G. Habermehl, i n The Alkaloids (R. H. F. Manske, ed.), Vol. I X , p. 427. Academic Press, New York, 1967. 246. K. S. Brown, Jr., i n Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 631. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 247. 0. Jeger and V. Prelog, i n The Alkaloids (R. H. F. Manske, ed.), Vol. VII, p. 363. Academic Press, New York, 1960. 248. S. M. Kupchan and A. W. By, in The Alkaloids (R. H. F. Manske, ed.), Vol. X, p. 193. Academic Press, New York, 1967. 249. V. Prelog and 0. Jeger, i n The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. 111, p. 247. Academic Press, New York, 1953. 250. J. Tomko and Z. Voticky, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XIV, p. 1. Academic Press, New York, 1973. 251. D. Lavie, i n Chemistry in Botanical Classification (G. Bendz and J. Santesson, eds.), p. 181. Academic Press, New York, 1974. 252. H. G. Floss, H. Guenther, and D. Erge, Int. Symp. Chem. Nat. Pvod. I U P A C , 5th, 1968 Abstract C3 (1968). 253. R. E. Schultes and A. Hofmann, The Botany and Chemistry of Hallucinogens. Thomas, Springfield, Illinois, 1973. 254. N. K. Hart, S. R. Johns, and J. A. Lsmberton, Aust. J . Chem. 21, 2579 (1968).
82
DAVID S . SEIGLER
254a. N. R. Farnsworth, N. K. Hart, S. R. Johns, J. A. Lamberton, and W. Messmer, Aust. J . Chem. 22, 1805 (1969). 25410. M. B. Mulchandani, S. S. Iyer, and L. P. Badheka, Phytochembtry 10, 1047 (1971). 255. S. R. Johns and J. A. Lamberton, i n The Alkaloids (R. H. F. Manske, ed.), Vol. XIV, p. 325. Academic Press, New York, 1973. 256. C. Poupat, B. Rodriguez, H. Husson, P. Potier, and M. M. Janot, C. R . Hebd. Seances Acad. Sci., Ser. C 269, 33 (1969). 257. N. Katsui, K. Sato, S. Tobinaga and N. Takeuchi, Tet. Lett. 6257 (1966). C 1091 (1971). 258. J. A. D. Jeffreys, J . Chem. SOC. 259. J. W. Cook and J. D. Loudon, in The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. 1 1 ,p. 331. Academic Press, New York, 1952. 260. W. C. Wildman, i n The Alkaloids (R. H. F. Manske, ed.), Vol. VI, p. 289. Academic Press, New York, 1960; Vol. XI, p. 307 (1968). 261. W. C. Wildman, in Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 151. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 262. J. W. Cook and J. D. Loudon, i n The Alkaloids (R. H. F. Manske and H. L. Holmes, eds.), Vol. 11, p. 331. Academic Press, New York, 1952. 263. W. C. Wildman, in The Alkaloids (R. H. F. Manske, ed.), Vol. VI, p. 247. Academic Press, New York, 1960; W. C. Wildman and B. A. Pursey, ibid. Vol. X I , p. 407 (1968). 264. W. C. Wildman, i n Chemistry of the Alkaloids (S. W. Pelletier, ed.), p. 199.. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 265. K. Krause, Die Natiirlichen Pflanzenfamilien, 2nd ed., Vol. 15a, pp. 227-386. Englemann, Leipzig, 1930. 266. E. Leete and A. R. Pinder, Chem. Commun. 1499 (1971). 267. A. E. Schwarting, i n Chemistry in Botanical Nomenclature (G. Bendz and J. Santesson, eds.), p. 205. Academic Press, New York, 1974. 268. B. Luning, Phytochembtry 6, 857 (1967). 269. B. Liining, i n The Orchids (C. L. Withner, ed.), p. 349. Wiley, New York, 1974. 270. L. A. Garay, Bot. Mus. Lea$., Ham. Univ. 19, 57 (1960). 271. L. Dressler and C. H. Dodson, Ann. Mo. Bot. G a d . 47, 25 (1960). 272. C. A. Bessey, Ann. Mo. Bot. G a d . 2, 109 (1915).
~ H A P T E R 2-
THE TROPANE ALKALOIDS

ROBERT L . CLARKE
Sterling Winthrop Research Institute Remselaer. New York
84 85 A . Proteaceae ..................................................... 85 B . Rhizophoraceae ................................................ 89 C. Solanaceae .................................................... 89 D . Euphorbiaceae ................................................. 92 E. E~throxylaceae ................................................ 92 F. Natural Tropane N-oxides ....................................... 93 G . A Secotropane ................................................. 94 1 1 1 . Syntheses ......................................................... 95 A. Oxallyl Additions to Pyrroles .................................... 95 B . Robinson Synthesis ............................................. 96 97 C. Dienone Amine Additions ........................................ D From Bridged Aziridines ......................................... 98 E . From Pyrrolidines .............................................. 100 F. Nitrone-Induced Cycloadditions .................................. 101 G. 1,3.Dipolar Additions .................... . . . . . . . . . . . . . . . . . . . 102 H . Nitrosation of Phenylalanine Tropanyl Ester . . . . . . . . . . . . . . . . . . . 104 I . Phosphorous and Sulfur Analogs .................................. 105 J Radiolabeled Tropanes .......................................... 106 I V . Reactions ......................................................... 107 A . Quaternization ................................................. 107 B. N-Oxides ........ .................................. 112 C. Nitroxide Radicals ....................................... . 114 D Cocaine Analogs . . ....................... 116 E Demethylation ................................................. 120 F. Reduction of Tropinone ............................... 123 G . Tropanyl Ethers ............................................... 124 H . Miscellaneous Reactions ......................................... 125 V Biosynthesis ...................................................... 136 A . Tropane Moiety ................................................ 136 B . Carboxylic Acid Moiety ......................................... 138 C . Transformations ................................................ 141 144 D. Tissue Culture Studies ........................................... E . Miscellaneous Biosyntheses ....................................... 146 VI . Biological Activit ........................................ 147 VII . Plant Content ... ........................................ 153 V I I I . Stereochemistry . ........................................ 155 162 I X . Analytical Methods ................................................ References .......................... ........................... 167
I. Introduction ...................................................... I1. New Tropane Alkaloids .............................................
. .
84
ROBERT L. CLABKE
I. Introduction
There have been four earlier reviews of the tropane alkaloids in this treatise, the latest having appeared in 1971 (I). The isolation of several new tropanes of surprisingly different structures, reports of many new tropane syntheses, a variety of novel reactions involving the tropane skeleton, and the many further investigations of plant content all prompt the updating of this subject while i t is yet of easily digestable proportions. A new series of volumes on alkaloids began in 1971 under the title The Alkaloids (London) and has appeared yearly. A section of each volume has been devoted to tropane alkaloids ( 2 ) . In the first and fourth volumes of this same series there appeared reviews on biosynthesis of alkaloids that contained sections on tropanes ( 3 ) .Biosynthesis of alkaloids is also being covered in review form in a series entitled Biosynthesis. Volume 2 has a section on tropane alkaloids ( 4 ) . Yet another review ( 5 ) on the present subject appeared in 1970 and a Russian book has been published entitled Physiology and Biochemistry of Tropane Alkaloids (6). The problem of searching the literature for tropanes, which always involved a vast number of trivial names, was simplified by Chemical Abstracts when it adopted the azabicyclo[3.2.lloctane system in 1972.
))
d
1
OCPh
Thus, cocaine (1) is methyl [1R-(exo, exo)]-3-benzoyloxy-8-methyl-8azabicyclo[3.2.1.]octane-2-carboxylate. However, the reader of a review on tropanes could get badly bogged down with interpreting these formal names, so it seems much more useful here to continue with traditional names. Readers are reminded that hyoscyamine is the naturally occurring, optically active form of tropine tropate, while atropine is the racemic form. The name scopolamine seems generally accepted as being synonymous with hyoscine, both referring to the 2-enantiomer. The dl-form is called atroscine (6a).However, a reported total synthesis of scopolamine described it as a racemic substance (6b).
2. TROPANE ALKALOIDS
85
II. New Tropane Alkaloids

A. PROTEACEAE
I n 1971, the first report of isolation of a tropane alkaloid from the family Proteaceae marked the beginning of a flurry of activity in this area. Some drastically different types of substituents on the tropane skeleton have been encountered and the first apparent racemic mixtures of naturally occurring, unsymmetrical tropane skeletons have been isolated.
1. Bellendena montana R . Br.
Bellendine, the first alkaloid to be isolated from the Proteaceae, has been shown to be 2,3-(2,3-tropeno)-5-methyl-y-pyrone (3) (7). Racemic bellendine has now been synthesized ( 8 ) starting with tropinone: Reflux of this ketone with sodium hydride in benzene for 20
(1) NaH
hours followed by treatment with 3-methoxymethacryloy1 chloride gave diketone 2. Acid catalyzed cyclization of the ketone afforded bellendine (3) in low overall yield ( 8 ) . The acylation process also produced some O-acylated material 4. Also isolated from this species were isobellendine ( 5 ) and cis-endodihydroisobellendine (6) ( 9 ) . The same group has indicated privately
86
ROBERT L. CLARKE
(10) that this source also provided three esters of tropane-3a,6/3-diol, namely the 3-acetate (7, R = H, R = CH,CO-), the 3-acetate-6and the 3isobutyrate (7, R = (CH,),CHCO--, R = CH,CO-), isobutyrate-6-acetate (7,R = CH,CO-, R = (CH,),CHCO-). The absolute configurations of these B. montana compounds have not been established.
6Rf
7
2. Darlingia ferruginea J. F. Bailey
The major alkaloid of this species, darlingine, is a methylated form of bellendine with the structure 8 (11).Analyses and spectroscopic data established its identity. It has also been isolated from D . darlingiana (F. Muell) L. A. S. Johnson (11).A minor constituent, called ferrugine,
\ Jc
CPh
proved to be 2a-benzoyltropane (9) (11). It appears to have a close biosynthetic relationship with the 2-benzyltropanes described below, but ferrugine shows [a]1f9 + 55O, whereas the 2-benzyltropanes appear to be racemates. If there is indeed a relationship between the two series, it will be interesting to find out whether ferrugine has the 1R or 1s configuration.
2.
TROPANE ALKALOIDS
87
Another surprise lay in the isolation of ferruginine (2-acetyltrop-2ene, 10) from this same species (10).
0
c & k c H 3
10
3 . Knightia deplanchei Vieill. ex Brogn. et Gris
A total of six new tropanes have been isolated from K . deplanchei that are unique in having a benzyl group on C-2. Four of these will be considered first (11, 12, 13, and 14) because the benzyl group is unsubstituted (12).
CHiPh
0
CHaPh 0 0-CCH,
12
OqPh
11
II
CH3
CH,N PhCO II \& ) T C H 2 h
rJ)T
OX\ 1;;
/H
OH
13
H
14
C==C / \
Ph
The nature and location of the substituents in these four compounds were established primarily by mass spectrometry with supportive evidence from IR,PMR, and hydrolytic data. All of these alkaloids showed zero optical rotations and are apparently racemates. The configurations of the various substituents were established later by 13C NMR spectral studies ( 1 2 ~ ) The . latter studies also distinguished the points of attachment of the hydroxyl groups on the ethylene bridges of 13 and 14.
88
ROBERT L. CLARKE
Compounds 11 and 12 were synthesized starting with tropinone and benzaldehyde (13). Although all earlier reports claim that only the 2,4-dibenzylidene derivative is formed in the reaction of these two substances, it was found possible in this case t o isolate 15% of the monobenzylidene ketone which was an ideal intermediate. Catalytic hydrogenation followed by reduction with lithium aluminum hydride (LAH) provided the four possible 2-benzyl-3-01s (see Eq. 1 ) . Benzoyla-
2 )
9 H P h
d
~
A)
CH,N
4CHzPh
LAH
0
2u and 28
J>q
CHaPh OH
2u, 3u
(1)
2ff, 38
28, 3a 28,38
tion and acetylation of one of these isomers (originally believed to have the 2/3,3cr-configuration) then gave 11 and 12, respectively, which corresponded to the natural products. Further studies of K . deplanchei have revealed two more racemic tropane alkaloids ( 1 4 ) .Owing to the small amounts of these compounds available only gross structures were determined. Spectral data on the natural bases and one hydrolysis product (from 15) indicated the gross structures 15 and 16 containing benzylic hydroxyl groups. A I3C NMR study of 16 established the detailed structure shown in that formula (12a).
2.
TROPANE ALKALOIDS
89
B. RHIZOPHORACEAE
Bruguiera sexangular (Lour.) Poir ; Bruguiera exaristata Ding Hou Several esters of tropine have been found in these two related species (15, 16). Esters identified were the acetate, propionate (a new natural ester), isobutyrate, butyrate (new), a-methylbutyrate or isovalerate (not differentiated), benzoate, and the 1,2-dithiolane-3-carboxylate (the major component, a new alkaloid called brugine). Studies on brugine showed that the skew sense of the C-S-S-C system is right handed in the 1,2-dithiolane-3-carboxylic acid portion of the ester (15). Optically active brugine has since been synthesized from 1,2-dithiolane-3-carboxylic acid of known absolute configuration (17) so that the natural d-alkaloid can be represented by 17.
017
C. SOLANACEAE
1. Datura suaveolens H. and B. ex Willd.
Some new esters have been isolated from D. suaveolens, a species indigenous to South America. From the aerial parts were isolated 3a,6/3-ditigloyloxytropane-7/3-ol (18, R1 = R2 = tigloyl), hyoscine, norhyoscine, meteloidine, atropine, noratropine, 1- and dl-3a-tigloyloxytropane-6/3-01 (not previously shown conclusively t o be a normal constituent of plant material), and a new alkaloid, 6p-tigloyloxytropane-3a,7P-diol (18, R' = H, R2 = tigloyl) (18).
OR'
0-C\
19
,c=c
,H
\
1s
CH3
CH3
90
ROBERT L. CLARKE
The roots of this plant were investigated by this same group (18). They yielded atropine (principal alkaloid), hyoscine, 3a,6/3-ditigloyloxytropane-7/?-01, meteloidine, cuscohygrine, and tropine, bases found in the roots of all Datura species previously examined. Also isolated were Three new bases tropine acetate and dl-3a-tigloyloxytropan-6/3-ol. were separated that had the characteristics of diesters of tropane-3a,6/3diol. One of these was shown to be the 6-(a-methylbutyrate)-3-tiglate 19.
2 . Datura innoxia Miller
A new base, present to the extent of only 0.00370, has been isolated from the roots of D . innoxia ( 1 9 ) .It was shown to be 6/3-propanoyloxy3a-tigloyloxytropane 20. Although the optical rotation of this diester
0-c,
CH,/
20
c=c /H \
CH,
21
OH
was O", hydrolysis revealed that it was derived from d-tropane-3a,6/3diol [lR-(3-endo-6-exo)]. The appearance of a propanoyl ester in the Solanaceae tropane series seems to be unique although 3a-propanoyloxytropane has been isolated from Bruguiera sexangular and B. exaristata (Rhizophoraceae)
(16).
3. Datura ceratocaula Jacq.
Datura ceratocaula, long known by the Mexicans as the narcotic torna-loca (maddening plant), has received little chemical attention, paper chromatography suggesting the presence of hyoscine, hyoscyamine, cuscohygrine, and four unidentified bases (20). Analysis of the aerial parts of mature D. ceratocaula plants by partition chromatography has now revealed (21)the presence of three bases in the ether eluate. The major base (0.00770) proved to be 6/3-(2-methylbutanoyloxy)tropan-3a-ol (21), constituted from d-2methylbutanoic acid and d-tropane-3a,6p-diol [ 1R-(3-endo-6-exo)].
2.
TROPANE ALKALOIDS
91
Biosynthesis of the acid moiety of this ester will be discussed in Section V. No information has appeared yet on the other two bases.
4. Datura sanguinea R. and P
a-Hydroxyscopolamine (21A) has been isolated ( 1 975) from the leaves of Datura sanguinea from Ecuador (22).The scopolamine from this plant is quaternized with n-butyl bromide to form a commercial antispasmodic drug. The reportedly new tropane alkaloid 21A was
OH
21A
first isolated in quaternized form as an impurity in the crude commercial product. Hydrolysis of this quaternary salt afforded known 2-phenylglyceric acid. Pure 21A, isolated from scopolamine mother liquors by preferential extraction a t pH 9 followed by chromatography, proved to be 400-fold less soluble in chloroform containing 2% ethanol than is scopolamine. No literature reference was recorded for this base (optically active). The dl-form of a-hydroxyscopolamine was reported six years earlier, its being prepared by hydroxylation of aposcopolamine (22a). Here again there was no reference to earlier preparations. On the other hand there is a Chinese report (1973) (copy not available) (22b)that describes the distribution of a-hydroxyscopolamine (called anisodine) in 19 genera and 54 species of Chinese solanaceous plants. A rapid scan of Chemical Abstracts formula and subject indexes revealed no further references to this compound. Anisodamine is a name given to tropane3a,6fl-diol 3-tropate (22c), the synthesis of which is described in this reference.
5. Physochlaina alaica E. Korot.
Physochhina alaicu has been found to contain 3a-(pmethoxyphenylacetoxy)-tropane-6fl-o1 (22), called physochlaine, together with some apoatropine (23).
92
ROBERT L. CLARKE
D. EUPRORBIACEAE Peripentadenia mearsii (C. T. White) L. S. Smith

Two new alkaloids were isolated from this Queensland tree along with tropacocaine (3~-benzoyloxytropane) (24).Although the identity of the specimen was confirmed, further collections of P . mearsii in the same area failed to yield any tropane alkaloids. One of the new alkaloids was d-tropane-3ct,6/3-diol 3-acetate (23) [1R-(3-endo-6-exo)J,identified by analysis, IR, NMR, and mass spectra and by comparison of its diacetate with the enantiomeric 1-tropane-3a76/3diol diacetate prepared from valeroidine by hydrolysis and acetylation.
OCOCH,
23
24
The absolute configuration of valeroidine was established earlier (25). This same ester was found in Bellendena montana (see above) (10). The other new alkaloid proved to be d-2~-benzoyloxynortropan-3fl-ol (24) of unknown absolute configuration. Initial structural studies were done on the natural alkaloid. It was then N-methylated (benzoate cleaved) and acetylated to give tropane-2a,3fl-diol diacetate which was used for the final structural studies (24).
E. ERYTHROXYLACEAE
Erythroxylum monogynum Roxb.

An ether extract of the alkaline root bark of E . monogynum was chromatographed to give five crystalline components of different
2.
TROPANE ALKALOIDS
93
molecular weights (26).One of these proved to be 3a-( 3,4,5-trimethoxyidentified by spectral and hydrolytic studies. benzoy1oxy)-tropane (25), Also present was 3a-( 3,4,5-trimethoxycinnamoyloxy)tropane(26),
CHsN
A %
O OCH, C H
2 %
0 O--CCH=CH Ii
OCH,
a5
26
OCHa
previously reported as a constituent of E . ellipticum leaves (27). The most recently reported compounds from E . monogynum are tropane3a,6p-diol 3-(3',4',5'-trimethoxycinnamate) 6-benzoate (26A), the first heterodiester to be found in Erythroxylum (27a) and tropane-3a,6p,7/3trio1 3-(3',4',5'-trimethoxybenzoate)(27b).
26A
OCH,
F. NATURAL TROPANE N-OXIDES

Until very recently there were no reports of isolation of tropane N-oxides from natural sources although several other types of alkaloids have been isolated in this form. I n one search for such tropane oxides authentic samples of the N-oxides of both hyoscyamine and hyoscine were prepared. Each formed a mixture of axial and equatorial oxides, the components of which were separated and characterized. With this reference background, both isomers of hyoscyamine N-oxide were isolated from the roots, stems, leaves, flowers, pericarps, and seeds of dtropa belladonna L., Hyoscyamus niger L., and Datura stramonium L. The equatorial AT-oxideof hyoscine was isolated from all parts of the latter two species and from the leaves of A . belladonna. The roots, stems,
94
ROBERT L. C W K E
and leaves of Scopolia lurida Dun. and S. carniolica Jacq. contained the two N-oxides of hyoscyamine and the equatorial oxide of hyoscine. Mandragora oficinarum L. roots, stems with leaves, and fruits contained both oxides of hyoscyamine. These oxides were probably missed heretofore because they are not soluble in the solvents customarily used for alkaloid extraction. The proportions of N-oxide to tertiary base varied among the organs examined and with different stages of plant development (28). Another oxide, 3a-tigloyloxytropane N-oxide (27), was isolated from the roots of Physalis alkekengi L. var. francheti Hort., formerly P .
J ) y J
0 4
J>x
04\
/C=c
11
/H
\
>Cd,
CH3
21
/H
CH3
28
CH3
CH,
bunyardii Makino. Also isolated were tigloidine (28), tropine, pseudotropine, an unidentified alkaloid, and the previously reported 3atigloyloxytropane (29). An investigation of Physochlaina alaica has revealed the presence of the N-oxide of 6-hydroxyhyoscyamine (30).
G. A SECOTROPANE
Physoperuvine (28A),a new alkaloid isolated from the roots of Physalis peruviana Linn., appears to be a biogenetic variant of the tropane alkaloids. The genus Physalis (Fam. Solanaceae) is well known for its elaboration of a novel group of C,,-secosteroids called physalins but its alkaloid content has not been determined. The structure of physoperuvine was established by NMR and mass spectral studies of
QNHCH3
QNTZ
0
Z8A
OH
Z8B
2.
TROPANE ALKALOIDS
95
the parent base, its N-benzoyl derivative, and of a methylated a,nd reduced form 28B. Present knowledge of biogenetic pathways to tropanes indicates that this alkaloid is a shunt product and not an intermediate in tropane biosynthesis ( 3 0 ~ ) .
III. Syntheses
A. OXALLYLADDITIONS TO PYRROLES
A new route to tropanes involved oxyallyl intermediates of the type
29 (L = Br, CO, solvent, etc. and R = alkyl) generated from a,a'-
dibromoketones and iron carbonyls. Trapping these intermediates with N-carbomethoxypyrrole or N-acetylpyrrole led to substituted tropanes (30) (31). The method suffered in that dibromoacetone could not be used to give tropanes without substituents a t C-2 or C-4.
29
30
A modified synthesis by the same investigators (32) allowed more generality. Thus, a,a,a',a'-tetrabromoacetone could be used to give a 2,4-dibromotropen-3-one (31). Debromination was accomplished essentially quantitatively to give 32 in SOY0 yield based on N-carbomethoxypyrrole.
31
32
A simultaneous investigation accomplished the synthesis using N-methylpyrroles and dibromoketones in the presence of sodium iodide and copper (33). The yields ranged from 50 to 89Yo. These reactions have the advantage of being run under neutral conditions.
96
ROBERT L. CLARKE
Another oxallyl equivalent is produced by treatment of silylated epoxide 32A with fluoride ion whereupon an allene oxide-cyclopropanone system 32B is presumed t o form. Trapping of this intermediate
?SiPh,
F__f
CH,CI 32A
A H
32B
P h b ]
with N-carbomethoxypyrrole afforded N-carbomethoxy-2-phenylnortrop-6-ene-3-one (32c) in 49y0 yield (33a).An earlier example of this type of reaction involved dimethylcyclopropanone (3%).
12c
B. ROBINSON SYNTHESIS
whereas earlier expansions of the classic Robinson synthesis (34) involved variation of the nitrogen substituent, a recent study (35, 35a) successfully ( 25y0 yield) substituted acetonylacetone for succindialdehyde. The optimum pH for production of 33 was 9.Use of heptane-2,Bdione and diacetonylsulfide gave 1 $-dimethylated granatanes and t hiagranatanes , respectively.
31
The same investigators (35) determined the effect of space requirements of the alkylamine on yield in the Robinson reaction:
Methylamine 100% Ethylamine 90% n-Propylamine 74y0 n-Butylamine 35y0 180-butylamine 22% Go-propylamine 50j, tert-butylamine 0%
2.
TROPANE ALKALOIDS
97
A polarographic study of the synthesis of tropinone by the RobinsonSchoepf method was used t o obtain optimum reaction conditions. Using a 15% excess of acetonedicarboxylic acid and 3% excess of methylamine a t 40C for 30 minutes gave an 82y0 yield of tropinone
(35b).
The synthesis of the optical isomers of tropan-2a-01 and tropan-2/3-01 on a large scale was studied from an economic standpoint (36).The most efficient route started with acetonedicarboxylic acid and 2,5-diethoxytetrahydrofuran in a Robinson-type synthesis and ultimately produced dl-anhydroecgonine amide (34). Rearrangement of this amide t o
34
35
dl-tropan-2-one and reduction t o dl-tropan-2a-ol by known procedures (37)gave the material chosen for resolution. Tartaric acid served as the resolving agent. The enantiomeric 2a-01s could then be epimerized to 2/I-ols (35) by strong alkali (37). One further slight modification of the Robinson-type synthesis has been reported (37a). C. DIENONE AMINE ADDITIONS The reaction of 2,6-cycloheptadienone (36) with amines has been studied further (38).See Fodor ( I )for earlier work. Dienone 36 reacted
36
37
38
with p-RC,H,NH, (R = MeO, Me, H, C1, NO,) to give corresponding N-arylnortropinones (37) in 45--93Yn yields. The lowest yield was obtained with p-nitroaniline. However, when even one equivalent of morpholine was added to 36, a 2:1 adduct (38) was formed. With two equivalents of morpholine, 38 was formed in 74y0 yield. Another study on addition of amines t o 36 was directed principally
98
ROBERT L. CLARKE
to the preparation of optically active compounds (39) (39) suitable for study of their circular dichroism (CD). Development of this mode of tropane synthesis was particularly useful for the large number of N-substituted derivatives desired (alkyl, aralkyl, cycloalkyl, carboalkoxyalkyl, and aryl). NMR data were fully discussed. CD information was published later (40) and is discussed in Sections IV-A and VIII. A further extension of this reaction involved addition of hydrazines and hydroxylamines to dienone 36 (41).Acetylhydrazine and 1)l-dimethyl and 40 (R = (CH,),N-), hydrazine gave 40 (R = CH,CONH-) respectively; hydroxylamine gave 40 (R = OH). 1,2-Dimethyl-
89
40
41
hydrazine, however, produced a diazabicydo[3.2.2]nonane ( 4 1 ) and N-methylhydroxylamine formed both possible N-oxides, 42 and 43. The picrate of the axial oxide shows no carbonyl absorption in its IR spectrum and presumably exists in the cyclic form 44 (41).
0
picric
X-
4L
43
44
D. FROM BRIDGED AZIRIDINES

5-Aminocycloheptene (45) was the starting material for another tropane synthesis (42). Lead tetraacetate converted this olefin to a bridged aziridine (46) which corresponds to the hypothetical aziridinium salt (47) proposed by Archer et al. (43) to interpret the ready racemization of d-2-tropanol acetate (48).
2.
TROPANE ALKALOIDS
99
46
46
(d)-48
47
(Z)-48
Reaction of the bridged aziridine 46 with diethyl pyrocarbonate followed by reduction (LAH) produced dl-tropan-2a-01 49. Quaternization of 46 produced 50 which reacted with sodium dimethyl malonate to form the tropanylmalonic ester 51.
EtOCON CH,N
49
CH,N
6!iFCH3
I50
NsC H ( C O 0 C H&
&
51
CH(COOCH3),
I n another transformation of aziridines into tropanes, ethyl 8azabicyclo[5.1 .O]oct-3-ene-8-carboxylate (51A) rearranged into N carbethoxynortropidine (51E) in the presence of dichlorobis-(benzonitri1e)palladium as catalyst. On the basis of NMR and product isolation studies the reaction appears to involve four steps. A palladium-7r olefin complex (51B)probably first forms which then undergoes attack by chlorine on the aziridine ring with cleavage of one C-N bond (giving 51C). Regioselective intramolecular attack on the olefinic bond by -NCOOEt furnishes tropane 51D, and loss of PdC1, gives the observed product. This postulated reaction course is supported by diversion of some of the intermediates with added reagents (43a).
100
ROBERT L. CLARKE
51E
51D
E. FROM PYRROLIDINES
An earlier study (1961) (44) of the reaction of cis-N-tosyl-2,5-bis(chloromethy1)pyrrolidine (52, R = tosyl) with phenylacetonitrile of the two possible (NaNH,, PhCH,) reported isolation of only one (53) isomeric products (28y0). Condensation of the corresponding N-benzyl-
r:
52
CH&l
N-R
+ PhCH,CN
+
Ph
CH&I
CN
53
64
pyrrolidine (52, R = PhCH,) with phenylacetonitrile in the presence of NaH and DMF allowed isolation of both isomers (53 and 54, R = PhCH,) (4107, combined yield) (45).The endo-nitrile 54 predominated threefold. Separation of the mixture of isomers could be accomplished by selective hydrolysis, the endo-nitrile being considerably shielded and difficult to cleave (1 hour a t 150C in 80% H,SO, for the p-nitrile; 48 hours under these conditions for the a-nitrile).
101
The degree of shielding of the 3a-position is such that the 3a-acid chloride can be recovered essentially unchanged following a 3-hour reflux period in EtOH (45). Esterification of the pair of acids formed from hydrolysis of 53 and 54 afforded two rigid analogs of meperidine (45)which are discussed in the section on Biological Activity (VI).The 13C and proton magnetic spectra of these esters are discussed in Section VIII.
F. NITRONE-INDUCED CYCLOADDITIONS
I n the process of a Cope rearrangement on 5-allyl-3,3,5-trimethyl-lpyrroline- 1-oxide (55)in boiling toluene the expected product (56) cyclized partially during the reaction to form isoxazolidine 57. The isolated nitrone 56 was slowly converted to cycloadduct 57 in boiling
__f
CH,
055 56
CH;
57
xylene. Reduction of 57 with LAH or Pt/H, afforded 1,6,6-trimethylnortropan-3/3-01 (58, R = H). Catalytic reduction of the methiodide of 57 gave 58 (R = CH,) (46).
RN
58
A similar cyclization was reported shortly thereafter. 4-Nitrobutene, upon reaction with acrolein in methanol containing sodium methoxide followed by acidification with dry HC1, afforded nitroacetal 59. This nitroacetal was converted to nitrone 60 by zinc (NH,Cl) and the latter was cyclized by heat to form isoxazolidine 61. Quaternization with CHJ and reduction with LAH then afforded tropan-3/3-01 (62)(47).
102
ROBERT L. CLARKE
62
G. DIPOLAR ADDITIONS
A communication and a follow-up paper (48) describe the synthesis of some tropanes (64, 65) that are considerably different from those found in nature. However, structural modification of natural tropane alkaloids is leading to compounds of such interesting biological activity (see Section VI) that it appears desirable to record all routes to this system. Anhydro-3-hydroxy-1-methylpyridinium hydroxide (63) reacts with N-phenylmaleimide, acrylonitrile, and methyl acrylate in the first examples of the C-6-N-C-2 unit of a simple pyridine ring acting as the 1,3-dipole in a dipolar addition.
Compound 63 reacted with phenylmaleimide in refluxing THF to form 64 in 60% yield, the ex0 configuration being demonstrated by NMR. In a similar manner (but with hydroquinone present) acrylonitrile added to form 65 with R = CN in an ex0 configuration. With methyl acrylate a 1:1 isomer mixture (R = COOMe) was reported. Dimethyl acetylenedicarboxylate gave only resinous products. Maleic anhydride formed a salt.
2.
TROPANE ALKALOIDS
103
Further studies on this reaction (49) involved the N-phenyl analog 66 which failed to react with maleic anhydride (see above) and merely formed a saIt. However, with N-phenylmaleimide, acrylonitrile, and methyl acrylate this betaine (66) gave the expected cycloadducts as mixtures of endo and exo isomers in good yields. Unlike the methyl
Ph
66
series, the isomers were easily separable and the structures could be confirmed by IR, mass, and NMR spectra. Attempted quaternization with CH,I failed, probably because of the large steric requirements of the N-phenyl group. In some related work on the N-phenyl analog 66, it was found that diethyl maleate and diethyl fumarate would react with 66 to form the expected 3-tropen-2-ones as mixtures of isomers (49u). I n a similar reaction N-carbomethoxy-2,3-homopyrrole 67 (R = H) reacted with N-phenylmaleimide (100C) to form a mixture of exo and
COOCH,
COOCH:,
p
67
68
endo isomers 68. This same pyrrole reacted with dimethyl acetylenedicarboxylate to form 69 (R = H). If the pyrrole 67 has R = COOCH,, this group assumes an ezo configuration in the product 69 (R = COOCH,). An intermediate dipole (70) is postulated for the reaction (50).
FOOCH,
I
COOCH,
COOCH,
CH30C C 0 II H
3
69
H R
70
H
/
104
ROBERT L. CLARKE
The work on 1,3-dipolar additions to form tropenones has been done principally by A. R. Katritzky's group, quite a few other papers by them having appeared. A review on the subject is now available (50u) which contains references to all pertinent publications so only one other will be described. Treatment of tropenone 70A with a very strong acid (CF,SO,H) caused cyclization with formation of 70B. Several analogs were prepared (50b).
a J -( -N
N
CF.SOaH
70A
70B
H. NITROSATION OF PHENYLALANINE TROPANYL ESTER

A synthesis of atropine (73),littorine (76), apoatropine (74), and related alkaloids has been accomplished (51)by a one-step deamination reaction of dl-phenylalanine 3a-tropanyl ester (72). This amino acid ester was obtained by coupling tropine with N-phthalyl-dl-phenylalanyl chloride 71 followed by hydrazinolysis with an equimolar amount of hydrazine hydrate.
PhCHa-CH-COCI
PhCHa-CH-COOR
O\
U0
N2H4
PhCH
CH-COOR
NHa
71
2.
TROPANE ALKALOIDS
105
Nitrosation of amino ester 72 using NaNO, and 2N H,S04 a t room temperature gave a mixture of six tropine esters, 7%78, two of which (73and 74) involved phenyl migration.
Ph4H-COOR CHzOH
73
Ph---CHz-CH-COOR OH 76 Ph4HdH-COOR
cis
Ph-G-COOR
72
EON0
___f
II
CHZ
74
77
tram8 78
Ph-CH-CH&OOR OH
75
A related synthesis of natural littorine and hyoscyamine also started with phenylalanine, in this case with the D-isomer. I n this sequence the amino acid was deaminated and the resulting phenyllactic acid was esterified with tropine, giving littorine. The tosylate derivative (78A) of this ester was solvolyzed with trifluoroacetic acid in the presence of sodium trifluoroacetate, phenyl group migration occurring in the process and producing the trifluoroacetate ester (78B) of hyoscyamine. Hydrolysis with aqueous HC1 then give hyoscyamine (51a).
az
00s
H+-O - T~
CH,Ph
78A
ooc
H++CH,OCCF,
II
ph
78B
I. PHOSPHOROUS AND SULFUR ANALOGS

Although the phosphorous analogs of natural tropanes are quite different from the natural alkaloids, it appears worthwhile to acknowledge their existence. Structures of types 79-82 have been prepared (52).
106
ROBERT L. CLARKE
0
R-P
II
79
80
81
82
Formulas 82A and 82B illustrate two of eight sulfur analogs of tropanes which have been synthesized (5%).
82A
82B
J. RADIOLABELED TROPANES
Acid catalyzed exchange tritium labeling of cocaine gave randomly labeled [3H]cocaine of 98y0isotopic purity and specific activity of 630 pCi/mg. Similar tritiation of ecgonine followed by esterification, benzoylation, and exhaustive purification provided ring-labeled [3H]cocaine of 99% isotopic purity and specific activity of 48 pCi/mg (53). Z-(p-Butoxybenzyl-a-t )hyoscyaminium bromide (83) was prepared by condensation of p-butoxybenzyl-a-t bromide with I-hyoscyamine in 40% yield. The tritiated benzyl bromide was prepared by reducing p-n-butoxybenzaldehyde with tritium-enriched hydrogen and treating the resulting benzyl alcohol with 48y0 HBr (54). Esterification of benzoylecgonine and benzoylnorecgonine with tritiated methanol afforded cocaine and norcocaine bearing a label on the methyl ester group ( 5 3 4 .
2.
TROPANE ALKALOIDS
107
The reaction of neonorpsicaine (84, R = H, R = C3H7)with CTH,I yielded [N-3H,-methyl] neopsicaine (84, R = CTH,, R = C3H7). In order to obtain a randomly labeled sample of psicaine (84, R = R = CH,) this compound was adsorbed on silica gel and exposed to tritium
2~3 ,
II
0 CHpOH 0--CCH-Ph 83
,CHT-CeH,OBu
Br-
J>x
COOR OCOPh
84
gas at room temperature for 11 weeks (modified Wilzbach method). Chromatography of the material eluted from the silica gel gave a 32y0 yield of single tlc spot psicaine with a specific activity of 90.7 mCi/gm corresponding to 30.8 mCi/mmole. The distribution of tritium in this [3H]psicaine in the benzoic acid, in the pseudoecgonine, and in the CH30 group was 84.5:11.5:4 (55).
IV. Reactions
A. QUARTERNIZATION
The stereochemistry of quaternization of tropanes has been the subject of controversy for quite a few years. Fodors 1971 review of tropanes in this treatise concluded that equatorial attack (with respect t o the piperidine moiety) predominated, although in many cases a substantial product was formed from simultaneous axial attack. The observed facts seem to indicate that diaxial interaction of the 28- and 4p-hydrogens with the approaching reagent is greater than that caused by the 68- and 78-hydrogens. Angular deformation of the five-membered ring helps to diminish this latter compression. Furthermore, the group already bound to nitrogen can accommodate more easily to 2,4-diaxial compression than the incoming group, which, in the transition state, is a charge-separated and solvated species ( 1 ) . I n a review on quaternization of piperidines in which tropane quaternization was discussed at about this same stage of development (1970) (56), McKenna still had some reservations about the steric course of these reactions. He concluded that, with a nitrogen atom
108
ROBERT L. CLARKE
positioned commonly to two different rings, qualitative predictions of stereospecificity are difficult. Another review appeared in 1970 by Bottini (57)who reported that the discrepancies in the controversy had been pretty well resolved and that equatorial attack seemed to be the predominant mode in tropane quaternization. He published a summary table showing reported quaternizations, reaction conditions, and product ratios. The possibility that it is the pyrrolidine ring of the tropane system that is the directing influence was considered by Otzenberger et al. (58). With tropane viewed as a piperidine, N-alkylation has t o be considered as primarily equatorial, in contrast t o the wealth of data demonstrating that piperidines undergo preferential axial alkylation. This anomaly can be eliminated, however, by considering tropane as a substituted pyrrolidine. Therefore, in this series we can expect axial alkylation. Bottini et al. (59) substantiated the configurational assignment of N-ethylpseudotropinium bromide by means of X-ray analysis. They also made the interesting observation that in the process of quaternizing tropinone there was an 88:12 equatorial: axial attack ratio at 70y0 reaction (30 minutes) and a 77:23 ratio at the end of 24 hours. With added tropinone or pyridine, this ratio fell to 50: 50. In this instance, an equilibration may be occurring through reverse Michael addition with transient formation of cycloheptadienone followed by readdition. Such addition of secondary amine salts to cycloheptadienone has been observed (38, 39, 41). Another example of this equilibration &furnished by Kashman and Cherkez who found that aqueous solutiens of N-[(AS)-a-phenethyllnortropinone methiodide underwent equilibration at room temperature in 48 hours to give a 40:60 mixture of 85 and 86, respectively. The equilibrium could be attained from either-ure isomer (40). This same work possibly provides a means for establishing the structures of certain isomeric quaternary salt pairs, namely through measurement of circular dichroism induced by a chiral center awched t o the nitrogen. A
85
86
2.
TROPANE ALKALOIDS
109
carbonyl group a t C-3 enhances this effect for that isomer with the chiral group in an axial configuration (85). Some further discussion of this work is given in Section VIII. Supple and Eklum (60) quaternized some tropidines (87) where the pathway for axial approach of the alkylating agent would be less
i R ,
p h c H h R
el
CH3
Br-
& -H c
e/
CHaPh
I-
87
88
89
hindered by axial hydrogens, whereas equatorial approach would suffer essentially the same interactions as in the tropanes. Larger proportions of products from axial attack might be expected. Treatment of tropidine (87, R = CH,, R = H) and 3-phenyltropidine (87, R = CH,, R = Ph) with benzyl bromide gave 92 and 91% yields, respectively, of the products resulting from equatorial attack (88, R = H and 88, R = Ph). The same predominance of equatorial attack was observed upon inverse addition of the substituents on the nitrogen. Thus, N-benzylnortropidine (87, R = PhCH,, R = H) reacted with methyl iodide to give 847, of 89. It should be kept in mind that the configurational assignments in the Supple-Eklum work are based primarily on the generally assumed principle that a reference compound, 3-phenyltropine, should quaternize principally by equatorial attack. In this series, the axial methyls were upfield of the equatorial methyls, a finding in accord with earlier reports from established series ( I ) . There were some NMR data on nonequivalence of ,certain benzylic methylene protons that strongly supported the assigned structures. Thut (61) studied the stereochemistry of quaternization of tropane, tropine, pseudotropine, and tropinone with ethyl haloacetates, benzyl halides, and benzyl benzenesulfonates but the results were inconclusive. A sophisticated I3C NMR study has just appeared that shows the practicality of determining configurations about the nitrogen of tropane quaternaries using this tool. The systems studied bore only alkyl groups on the nitrogen (61a).For further details see Section VIII. At this time, there seemed to be a rather consistent picture of predominantly equatorial attack with respect to the piperidine moiety in tropanes. But in 1974, a report by Szendey and Mutschler (62)
110
ROBERT L. CLARKE
appeared that stated that benzylic bromides reacted with tropine principally by axial attack. The direct reaction (Eq. 2) gave the isomers shown with a selectivity of 98,96, and SOYo, respectively for R1, R2, and R3. The previously reported patterns of quaternization ( I ) and observed downfield locations
R(1.2.3)
e/
dH
dH
R = PhCHiR2 = PhCeH4CHzR3 = -CH~CBH,CBH*CH~ -
(NMR) of methyl groups (1)(versus the reverse isomers) would lead ordinarily to assignment of configurations opposite t o those shown here. However, the authors made their structural assignments on the basis of mass spectral fragmentation patterns. Their basic assumption was that equatorially bound ligands would have a higher energetic stability than the axial ligands, and thus a greater amount of RBr (or fragments thereof) than CH,Br would appear from the above isomers. In like manner, the isomeric forms (90) would produce a preponderance of CH,Br.
R(1.2.W-N
e/
CH3
OH
90
The mass spectral data (reported for R2 and R3) showed consistent patterns that were considered valid enough to use as a basis for assignment of the structures shown. Unfortunately, there are no data available on mass spectral fragmentation patterns of quaternary salts of proven configuration. Even so, it would be hazardous to extrapolate those data to these benzylic systems. Hopefully it will be possible to settle this question eventually by X-ray analysis.
2.
"ROPANE ALKALOIDS
111
Referring again to the work described above by Supple and Eklum (60), those authors found that direct benzylation of tropidine with benzyl bromide gave a 92: 8 isomer mixture and that methylation (CH,I) of N-benzylnortropidine gave a 16:84 mixture, i.e., a considerable predominance of specific attack in each case. Szendeyand Mutschler (62)found that benzylation of tropine gave a 98: 2 ratio of products but that methylation (CH,Br) of N-benzylnortropine gave a 55: 45 ratio (rather nonstereospecific). Reaction rate measurements were used by Weisz et al. (63)t o determine the effect of various substituents in the tropane skeleton upon the reactivity of the tropane tertiary nitrogen. Cocaine (91) and ecgoninol (92), with axial substituents on C-2, react slowly with CH,I a t room
CH,N
s;J
OCPh
91
2 )
92
JOH
OH
temperature and not a t all with ethyl iodoacetate. [This reaction selectivity was used elsewhere to separate a mixture of tropanes that were epimeric at C-2 (64).] Likewise, the two p-hydroxyl groups of teloidine (93, R = a-OH) and teloidinone (93, R = 0) greatly hinder quaternization. But surprisingly, the single 6j3-hydroxyl function of
HO R H > lJ
H o J ? T
R
93
94
3a,6p-dihydroxytropane (94, R = a-OH) and 6p-hydroxytropinone (94, R = 0) does not affect the rate of methylation as compared with the corresponding derivatives containing no 6p-hydroxyl group. Under more vigorous conditions (SOT), ecgoninol diacetate reacts with ethyl iodoacetate (65), but in boiling toluene this addition is reversed (66). The preparation of quaternary salts is often complicated by accompanying dehydrohalogenation of the alkyl halide used. A hydrohalide salt of the tertiary amine then precipitates together with the quaternary. It has been found that addition of ethylene oxide to such reaction
112
ROBERT L. CLARKE
mixtures acts as a scavenger of the acid, regenerating the amine which is again free to quaternize. 1-Scopolamine was quaternized with 3,3dimethylallyl bromide, (2-methylcyclopropyl)methyl bromide, cyclobutylmethyl bromide, and 2-cyclopropylethyl bromide to give the corresponding quaternary salts in 66,48,51, and 61% yields, respectively (67). . . Tropine, atropine, and hyoscyamine were treated with propanesultone(1,3) and butanesultone-(1,4)to give inner salts of type 95 where n = 3 or 4. These crystalline salts were quite soluble in most common organic solvents and had high melting points (68).
CH3 (-)O&I--(CH~)~-N,
Ll
OR
95
B. N-OXIDES
A reaction related to quaternization and one that raises the same questions about stereochemical course is the formation of tropane N-oxides. The major product from the N-oxidation of scopolamine has been fully characterized by X-ray crystallographic analysis in the form of 1-scopolamine N-oxide hydrobromide monohydrate. I t s N-methyl group is axial and the oxide function is equatorial (96).
0
) Jo
&- o
0 CHaOH
OR
96
R = -G-CH-Ph
II I
OR
97
Huber et al. went on to examine by 100 MHz NMR spectroscopy the crude reaction mixtures from oxidation of scopolamine, atropine, and tropine (H202 in EtOH at 30C). Both atropine and tropine gave product ratios of 3:l of the N-oxides, the major N-methyl resonances
2.
TROPANE ALKALOIDS
113
being a t lower field in each (AS = 0.1 and 0.03 ppm, respectively). I n contrast, the methyl resonance of the major oxide from scopolamine appears a t higher field (AS = 0.21 ppm). Assuming that the major product from atropine and tropine has an equatorial oxide configuration, it must be concluded that the epoxide oxygen of the scopolamine deshields the equatorial methyl of (97) and causes the observed reversal of methyl signals in that substance relative to tropine and atropine (69). Isomeric pairs were not isolated in pure form. About the same time Werner and Schickfluss (70) described the oxidation of tropine with H202in EtOH (reflux) with actual isolation of the two possible N-oxides. On the basis of their NMR spectra (100 MHz but not very well defined), the major product (65y0) was tentatively assigned the configuration with oxygen axial; the minor product (2.8y0) was drawn with the oxygen equatorial. No interpretation was given to the N-methyl peak positions. The configurational assignments [the reverse of the assignments for tropine in the study just described (69)l were made on the basis of the positions of what were assumed to be the C-2 and C-4 axial hydrogen peaks. A 220 MHz study by Bachmann and Philipsborn (71) of this same pair of isomeric N-oxides (one pure; one a 2 : l mixture) gave very clear spectra that allowed assignment of each hydrogen resonance. The fallacy in assignment of the C-2 and C-4 axial hydrogen peaks in the 100 MHz work just described was demonstrated and the major product was shown to have the oxygen actually in the equatorial configuration. This equatorial oxygen deshields the 6/3 and 78 hydrogens quite significantly. The N-methyl peaks are reported with a difference of only 0.01 ppm, the major product (axial methyl) being a t lower field. The final chapter of this particular story was written by Werners group recently (71a) when dipole moments were determined on both pure isomers, X-ray structure analysis was performed on one of these and 200 MHz NMR spectral studies were made of both isomeric [2,2,4,4-D4]tropine-N-oxides. The assignments of the Huber, the Bachmann and the Werner groups are now in agreement. Yet another study of tropine N-oxides was not very satisfactory since the isomers were not separated (72).An analytical procedure for the determination of N-oxides such as t,hose from atropine and scopolamine involves controlled potential coulometry (73). The isolation of some N-oxides from plant sources was described in Section 11, F (28-30). Although an earlier report expressed preference for H,02 over m-chloroperbenzoic acid for N-oxide formation (69), the most recent paper on the subject recommended the peracid (28).
114
ROBERT L. CLARKE
C. NITROXIDE RADICALS
Stable dialkyl nitroxide radicals other than sterically hindered di-tert-alkyl nitroxides were unknown until 1966. Those nitroxide radicals that were unstable (98) appeared to decompose by dismutation t o a nitrone (99) and a hydroxylamine (100) or, a t least, to involve a nitrone as an important intermediate. A clever solution to the stability
98
99
100
problem was achieved through the synthesis of norpseudopelletierineN-oxyl (101), a ring system that does not allow formation of a double bond between the nitrogen and an adjacent carbon (Bredt's rule). This radical, although stable in the solid state and in benzene or water solution, is very reactive (much more so than the related 2,2,6,6tetramethylpiperidine-N-oxyl), and the ESR absorption disappears rapidly in acidic or in basic solution (74). The same group went on to study 1,5-dimethylnortropinone-N-oxyl (102) and determined all proton hyperfine splitting constants with
0.
0.
N
101
102
magnitude and sign and with complete specific assignments ( 7 5 ) .X-ray analysis of this N-oxyl (76) has shown that the N-0 bond (103) is inclined a t an angle of 24.9" to the plane of C-1-N-C-5. This angle is comparable with those shown by other nitroxyls and is less large than that of 30.5" shown by granatane-N-oxyl. As in the granatane case and contrary to the finding with pseudotropine, the N-0 bond is inclined toward the ring containing the carbonyl group. This inclination has been predicted by calculation of conformational effects (75). Nortropine-N-oxyl was reported in 1970 from oxidation of nortropine with 307' H202 in the presence of NaWO,. Its EPR spectrum was shown (77).
2.
TROPANE ALKALOIDS
115
101
104
The first of a series of papers by a Canadian group (78) reported that nortropane-N-oxyl (104) is stable a t room temperature in neutral solution. Since the electron paramagnetic resonance signal due to this radical in solution could be reversibIy decreased and increased by cooling and warming, it was assumed that 104 could form a diamagnetic dimer at low temperatures. The free nitroxide radical is relatively more abundant below room temperature in CF,Cl, than in isopentane. During the course of studies on this reversible dimerization of nortropane-N-oxyl(79), it was discovered that an irreversible dimerization was occurring. This change was accelerated by heat but transpired fairly readily at room temperature in CC1, (80y0 in 12 days). The principal dimeric product was 105. However, when dimerization took place in the presence of silver oxide, a second dimeric product (106) was isolated (dark red crystals, 2%). It was also noted in this report that
0
? @
nortropane-N-oxyl oxidized aqueous hydrogen peroxide rapidly a t room temperature with copious gas evolution, whereas 2,2,6,6-tetramethylpiperidine-N-oxyl was inert t o these conditions. The material in the communication just discussed (79) is reported in more detail in two follow-up papers (80).Here, the N-oxyls of nortropine and norpseudotropine were also described. Labeling studies showed that the bridgehead hydrogens were not involved in the irreversible dimerization t o form 105. The most recent paper in this Canadian covers some calorimetric and equilibrium studies on nitroxide series (81)
h
105
fjqJ
106
116
ROBERT L. CLARKE
and iminoxy radicals. Equilibrium constants are given for some radicaloxime reactions in benzene where nortropane-N-oxyl is one of the radicals utilized. Excellent yields of nitroxides in nonaqueous medium have been obtained with m-chlorobenzoic acid and with CH,CN-CH,OH-WO, (very little water) (81~). Electrochemical oxidation of seven different nitroxyl radicals (two tropanes) has been investigated in CH,CN with a platinum electrode. The oxidation is a reversible, one-electron process leading to an oxammonium ion (Eq. 3) (82).
D. COCAINEANALOGS
Some cocaine analogs have been prepared for biological purposes ; the testing results are described in Section VI. However, the chemical reactions are appropriately detailed here. Benzoylation of tropane-ZP,3p-diol with one equivalent of benzoic anhydride with a routine work-up gave the 3-benzoate (107) as the major product together with a small amount of 2-benzoate (108) and a very small amount of dibenzoate. It was shown that the %benzoate is
107
108
intermediate in the formation of the 3-benzoate. Acetylation of these benzoates then gave some reverse-ester analogs of cocaine (83). 8-Ethoxycarbonylnortropane-2/3,3/3-diol, an intermediate used in the synthesis just described, reacted with variously substituted benzaldehydes to form isomeric acetals 109 and 110 (R = EtOCO-). Configurations were assigned to these isomers on the basis of NMR data. Lithium
2.
TROPANE ALKALOIDS
117
109
110
aluminum hydride converted them to the corresponding N-methyl acetals 109 and 110 (R = CH,). Acetals 109 and 110 (R = EtOCO-) were converted by N-bromosuccinimide (BaCO,) into a single bromoester, 111, which was transformed by aqueous alcoholic potassium carbonate into the 2/3,3,%epoxide
Br
111 112
112. Hydrolysis of this epoxide produced a diaxial diol, 113, which failed t o form acetal 114 (Eq. 4). Such acetal formation would have required a boat conformation for the piperidine moiety (84).
EtOCN
I\
OH
EtOCN
II
113
OH
114
A series of central nervous system stimulants was prepared in which the elements of COz were (formally) removed from cocaine, i.e., the aromatic ring was attached directly to carbon-3. Phenylmagnesium bromide reacted with anhydroecgonine methyl ester (115) in ether a t - 20C in the absence of copper salts to form a 1:3 mixture of 28carboxylate 116 and 2a-carboxyIate 1I?. Structural assignment was based upon NMR data and reduction to the corresponding alcohols (118 and 119), one of which showed intramolecular hydrogen bonding.
118
ROBERT L. CLARKE
CH,N
\\
,COOCH3
115 115
4
PhMgBr
116
CH,N
I\
COOCHj
Ph
117
The axial ester 116 quaternizes more slowly than the equatorial ester 117,a fact that can be used to separate isomer mixtures when it is desired to recover only the axial (stimulative) isomer. Attempts to influence the ratio of isomers formed in the Grignard reaction failed (64).
z)<ph
-**H-o\
118 120
3)XYH
119
Treatment of either the axial ester 116 or the equatorial ester 117 with polyphosphoric acid at 150C produced a single product, a 1,3ethanoindeno[2,1-c]pyridine, 120. A series of such compounds was studied for analgesic activity (85).
In 1896 tropan-3-one was found to react with HCN to form a single crystalline cyanohydrin (86).Only one crystalline isomer was obtained by addition of HCN to nortropan-3-one many years later (1957) (87), and both compounds were shown to belong to the same series, i.e., a-cyano-p-ols (121). These cyanohydrins were then converted by
119
CN
121 122
COOCHB
conventional means to a position isomer of cocaine called a-cocaine (122). Recently, N-benzylnortropan-3-one was treated with HCN and, when the adduct could not be induced to crystallize, the crude oil was hydrolyzed with concentrated hydrochloric acid and the resulting carboxylic acid was esterified (see Eq. 5 ) . Both of the possible epimers were isolated (123 and 124). Presumably both cyanohydrins ordinarily
CN
COOCH,
123
OH PhCHaN
OH
124
120
ROBERT L. CLARKE
form, but if one crystallizes (as was the case with tropan-3-one and nortropan-3-one), the equilibrium is shifted and little of the other epimer remains. Hydrolysis of the oily N-benzyl cyanohydrin was thus able to provide both forms. The new ester (124) afforded an opportunity to make the unknown /?-cocaine. Benzoylation of the axial hydroxyl group proved difficult, but treatment with potassium hydride followed by benzoyl chloride was effective (see Eq. 6 ) . Debenzylation and methylation then afforded /3-cocaine (125) (88).
PhCH&,
(1) K H
( 2 ) PhCOCl
(1) H d P d (2) HCHO HCOOH
COOCH, I OCOPh
OCOPh
125
E. DEMETHYLATION
For many years the primary route to nortropanes lay in demethylation of tropanes by KMnO,, K,Fe(CN),, or cyanogen bromide. Another method, which has found little use (89), was first reported in 1927 (90). The N-oxides of several tropanes were treated with acetic anhydride and the resulting N-acetylnortropanes were hydrolyzed (see Eq. 7) (89).Trifluoroacetic anhydride has also been used in this transformation (29). The usefulness of these early methods should not be discounted. Proper control of pH in the oxidation of cocaine by permanganate has furnished a yield of norcocaine based on recovered starting material ( 9 0 ~ ) .
2.
TROPANE ALKALOIDS
121
Recently, the use of chloroformic esters has become the method of choice (83,91-93).Although ethyl chIoroformate reacts with tropan-3a01 acetate to give urethane 126 in high yield, the same reagent reacts with tropan-3a-01 (the free alcohol) to produce a large amount of
0 E t O J )
It
~,
OAc
126
0
E t J )
II
3 )
~
OH
127 128
OH
resinous material and only a little of the desired urethane 127. Both products, however, are easily hydrolyzed with strong hydrochloric acid to nortropan-3a-01 (128). With tropinone, the ethyl chloroformate reaction goes well, but the hydrolytic step fails to produce any of the desired nortropinone (93). This problem in demethylation of tropan-3-one has been solved by formation of an ethylene ketal (129), which reacted cleanly with ethyl
0
II
129
130
131
chloroformate. The resulting urethane (130) was then hydrolyzed with potassium hydroxide to generate the nor product (131).Acid hydrolysis removed the protecting group (94). Another variation of the N-demethylation procedure utilizing alkyl chloroformates involved phosgene. Thus, treatment of tropan-3-one in toluene at 10C with phosgene in toluene and heating the product in water until CO, evolution ceased gave nortropan-3-one. The hydroxyl group of scopolamine was protected by acetylation prior to phosgene treatment (95). It should be noted that benzyl chloroformate gave very poor yields of urethanes in the demethylation procedure under discussion (96).
122
ROBERT L. CLARKE
Phenyl chloroformate gave good yields a t room temperature (92),and vinyl chloroformate was quite effective, reacting exothermically a t room temperature (96). 2-Chloroethyl chloroformate was used to demethylate a 3-phenyltropane-2-carboxylic ester with the expectation that the resulting urethane (132)could be cleaved with zinc and alcohol, thus avoiding hydrolysis with strong acid which would attack the ester. When zinc
0
132
133
and alcohol (or acetic acid) failed to effect reaction the function on the nitrogen was cleaved with chromous perchlorate (64). It turns out that 2,2,2-trichloroethyl chloroformate is the reagent of choice for tropane demethylation. It produced from tropinone a good yield (95y0) of trichloroethyl carbamate (133) which was easily cleaved by zinc in methanol or acetic acid (62%) (97). In addition to their usefulness as intermediates in the preparation of nortropanes, the urethanes under discussion can be reduced with lithium aluminum deuteride to form labeled tropanes. Thus, Nethoxycarbonyltropine is converted ( 66y0) to 133A (97a).
OH
133A
In the von Braun demethylation procedure, an intermediate Ncyanoammonium salt structure has been considered probable. Such intermediates have been isolated as crystalline solids by combining tropine, pseudotropine, and tropinone with cyanogen bromide at - 50C to - 60C. These salts ordinarily decompose near 0C to give N-cyanoamines and CH,Br. However, conversion to fluoroborates (AgBF,) effected considerably greater stability (98).
123
Photooxidation of tropinone (98a), tropan-3a-01, tropan-3/3-01, and deoxyscopoline (98b) has caused N-demethylation. The presence of a benzoate chromophore as found in cocaine, benzoyltropine, and benzoylpseudotropine aids in the removal of the N-methyl group. Cocaine yielded 20y0norcocaine together with 70y0 recovered cocaine. It is not necessary that the benzoyl group be in close proximity to the N-methyl reaction center but the specificity of the reaction for bicyclic compounds with N-methyl bridges compared to monocyclic ones is apparently due to the operation of Bredts rule on a proposed imine intermediate (98c).
F. REDUCTION OF TROPINONE
Until recently, reduction of tropinone to tropine with high stereoselectivity has been achieved only by catalytic reduction (see 99). T h i s selectivity depends upon the presence of the basic nitrogen as evidenced by the fact that 8-ethoxycarbonylnortropan-3-one is reduced by Pt/EtOH (or HOAc) to give a 3:l mixture of the 3a- and 3p-01~ respectively (83).A stereoselective chemical reduction has now been described. Diisobutylaluminum hydride in tetrahydrofuran a t - 78C reduces tropinone to form of the 3a-01 accompanied by only 3y0 of the 3p-01 (100).Another example of this is described by Noyori et al. (32). In a comparison of various methods of reduction of tropinone the results tabulated below were obtained (29).
~~
3a/58-01
Reagent Na/EtOH Na/i-BuOH Hz, PtOa, EtOH Hz, PtOa, EtONa NaBH,
Ratio 1/24 1/27 99.410.6 1211 54/46
A somewhat surprising catalytic hydrogenolysis of ketone to methylene has been reported (101). Tropinone, tropan-6-one, and 6p-hydroxytropinone are reduced to tropane, tropane, and tropan-6p-01,respectively, by hydrogen in the presence of PtO, in weight equal to that of the ketone and a molar excess of acid. The obvious alcohol intermediates in the reaction are untouched by the reaction conditions. Earlier examples of this type of reduction are to be found in some work on cyclitols (102).
124
ROBERT L. CLARKE
I n a reaction conducted on a thin-layer chromatographic plate, tropinone was reduced with a NaBH, spray reagent a t 50C. The products were then separated by normal plate development (103). Photochemical studies indicate that /?-aminoketones (especially tropinone) are subject t o photochemical reduction, probably yielding a highly fluorescent p-amino alcohol among the reaction products (103a).
G. TROPANYL ETHERS
Until fairly recently there was no good general method for preparing tropanyl ethers. I n 1968 a report appeared (104) of the conversion of 3a-chloro-, 3a-bromo-, and 3a-mesyloxytropanes into 3a- and 3/?-phenyl, n-butyl, methyl, and thiophenyl ethers in moderate (21-48y0) yields with concomitant elimination and fragmentation. More recently, this same group published four papers (105-105c) that described many more ethers and showed that (a) for strong nucleophiles (PhO-, PhS-), S,2 reactions predominated over SN1 and gave /?-substituted tropanes; (b) weaker nucleophiles (CN- , N3-) involved both mechanisms; (c) with compounds containing basic nitrogen (PhCH,NH,, PhCH,CHMeNH,) the SN1 mechanism predominated, giving a-derivatives; (d) the character of the displaced group played a role, i.e., PhO- reacted with the 3a-mesylate with inversion but with the 3a-chloride with retention of configuration. I n configurational studies it was shown by dipole moments that a C-3 phenoxyl group in the a-orientation causes considerable distortion of the tropane skeleton. The mechanism for formation of benzhydryl ethers from /?-dialkylaminoalcohols has been postulated (1054 as involving initial formation of a quaternary ammonium salt followed by a nucleophillic attack by oxygen on the tertiary carbon atom and extrusion of the nitrogen (see I33B). Since such a mechanism would be impossible in the formation of 3a-tropinyl o-methyl-0-methoxybenzhydryl ether (133C), only a direct attack on oxygen can be considered (105e).
l33B
133C
2 .
TROPANE ALKALOIDS
125
Another approach t o ether formation at C-3 featured treating the anion from 8-benzylnortropane-3a-01 (or ,9-01) (134) with m- or p fluorobenzotrifluoride (135) in dimethylformamide a t 60-70C (see Eq. 8). The ethers produced (136) have the same C-3 configuration as that of the tropanol used. The benzyl group was then cleaved and other substituents placed on the nitrogen for biological studies (106).
PhCH,N
Apq
134
+ q c F 3 - p h ~ k i o d
(8)
0135
/ \
136
H. MISCELLANEOUS REACTIONS
A study of asymmetric induction involving an optically active Wittig reagent [( R)-benzylidenemethylphenylpropylphosphorane (137)] included its reaction with tropan-3-one to produce optically active 3-benzylidine-8-methyl-8-azabicyclo[3.2. lloctane (138) of unknown configuration and optical yield (107).
CH3N, Ph\+ C3H,-P-C CH,/
-/
Ph H
137
138
Willstgtter et al. (108) obtained an unknown crystalline product by benzoylation of methyl 3-oxotropane-2-carboxylate (139). PMR and IR spectrometry have shown (109)this product t o be methyl 3-benzoyloxytrop-2-ene-2-carboxylate (140). Attempted hydrogenation of 140 to a cocaine epimer failed.
CH3N
4>---qXOCH3
&
COOCH,
0 OC-Ph II
139
140
126
ROBERT L. CLARKE
The preparation and characterization of the tropic acid esters of tropan-3j3-01and granatan-3a and 3p-01 are described (110). Earlier efforts to prepare tropane-3j3-aceticacid (141) had given very poor yields (111). Further studies have developed a satisfactory route to the corresponding 3a-acetic acid 142 (llZ), but none of the 3j3 epimer.
CH,COOH
141 142
N-Acetylnortropanone (143) reacted with malononitrile in the presence of piperidine and acetic acid to form a dicyanomethylene derivative (144). Catalytic hydrogenation followed by acid hydrolysis led exclusively to the 3a-acid 142 (Eq. 9).
CH,CON
143 144
142
(9)
* c H o -* \
\CN ,CN
Addition of HCN to the dicyanomethylene intermediate 144 gave trinitrile 145, which hydrolyzed and decarboxylated to form dicarboxylic acid 146 (Eq. 10). Attempts to esterify this dicarboxylic acid failed.
144
CHaCON
H $ c -< J ) ;
CN
145
$ H + c ) J
CH,COOH
(10)
COOH
146
Approaches to the 3j3-aceticacid 141 through halomethyl or tosyloxymethyl intermediates (147, R = C1 or OTs) failed owing to ready quaternization forming 148 (Eq. 11).
2.
TROPANE ALKALOIDS
127
R148
(11)
147
This problem of intramolecular alliylation in the synthesis of 3/3substituted tropanes was avoided by protecting the nitrogen with a tosyl group. Tosylated nortropane carboxylic ester 148A was reduced to tropanemethanol148B which was then sequenced through R = OTs,
TsN
RN
148A
148B, R = Ts, R = O H 148C, R = H,R = COOH
R = CN and R = COOEt to 148C, the acid desired earlier. The tosylate group was removed in the process of nitrile hydrolysis. The /?-configuration of the acetic acid group was demonstrated by converting the 3/3-acetic ester substituent above to hydroxyethyl, to chloroethyl (148D), and finally (cyclizing) to tropaquinuclidine 148E (112a).
HN
148D
148E
Several dl-tropic acid esters of tropan-3-01s were prepared by a transesterification procedure. Thus, tropine reacted with the aldehydoester 148F to form tropine ester 1486 (R = CH,). Reduction of the aldehyde function then gave atropine. The method was applied to
CHO Ph-CH-COOCH, 148F
128
ROBERT L . CLARKE
nortropan-3a-01s carrying a broad variety of groups on the nitrogen. N-isopropylnortropan-3~-01underwent the same transformations (112b). Tropane-3,6-diol esters were used to demonstrate the selective hydrolysis of dihydrocinnamate esters (DHC) by a-chymotrypsin. The mixed ester 149 was hydrolyzed only at position 3 by a-chymotrypsin,
ODHC
149
a-chymotrypsin
Y-
OH
150
151
ODHC
forming 150. Carefully controlled basic hydrolysis gave selective cleavage a t position 6 with formation of 151 (113). Solvolysis of unsaturated tosylate 151A in 70ojb aqueous dioxane occurred 2.1 x lo5 faster than did solvolysis of its saturated analog 151B. The reaction involving the saturated tosylate 151B produced only
OTs
l5lA
CHz\OTa
151B
a trace of the parent alcohol together with 37% of 3-methylenetropane, 20y0 of 3-methyltrop-2-ene, 9% of 3,8-methyltropan-3a-01,and 10% of 3a-rnethyltropan-3/3-01.Synthesis of the required tosylates was accomplished via hydroboration of appropriate 3-methylene intermediates (113~).
2.
TROPANE ALKALOIDS
129
Grignard reactions on tropinone have not been very satisfactory, presumably owing to formation of insoluble complexes with the amine moiety prior to reaction. Conversion of tropinone to urethane 152 by means of ethyl chloroformate gave a neutral ketone that reacted with aliphatic Grignard reagents to form 153 in moderate yields (R = benzyl,
0 EtOCN
II
II
h0
152
153 o
OH R
50%; R = methyl, 32%; R = ethyl, 33%; R = propyl, 23%). Although the urethane moiety was claimed not to be attacked, some 4070 of the reactants were not accounted for in the highest yield reported. The single isomers isolated were presumed to have axially oriented hydroxyl groups; with 153 (R = benzyl), the orientation was proved (114). A spiro tropane (154) was prepared by the following sequence of reactions (Eq. 12) (115). The authors were not aware of the Heusner
CH,NH2
CH2-NH I54
work on HCN addition to tropinone (87) and agree (private correspondence) that the configurations shown here a t C-3 are correct. I n a second phase of this work, butyronitrile was condensed with tropinone.
130
CHsN
ROBERT L. CLARKE
CH3N
CH3N
& h + , A l H CH&H&HCN
155
A+,HO CH,CH&HCONHp H
CpHs-CH / o \c NH i N
156
157
The resulting cyanoalcohol (155) was hydrolyzed (156) and converted to oxazolidone 157. On the basis of present information, the configuration at C-3 in this series remains unproved.
e
CH3N
~ 1 1 ~
+~
CH,CI,
H . - Q - ; ~ N H ~ __t
NH
&so30
158
PH3
Tropinone reacts with O-(mesitylenesu1fonyl)hydroxylamine in to form (80y0)a hydrazinium mesitylenesulfonate (158). N-Amination appears to proceed faster than oxime formation. The configuration about the nitrogen was not determined (116). Pyrolysis of the hydrochloride of ethyl 3a-phenyltropane-3j3carboxylate (159) caused ring cleavage and chlorine insertion with formation of pyrrolidone 160 (117).
.HC1
COOCaH,
159
4
-
160
The racemization of hyoscyamine has been studied in refluxing methanol, isobutyl alcohol, toluene, and dioxane (118). Racemization in water was studied earlier (119). In some microchemical investigations of medicinal plants (120), scopolamine was hydrolyzed in microgram amounts with Ba(OH), a t
2.
TROPANE ALKALOIDS
131
25C in I hour to give scopine. At 100C the main product was scopoline. Atropine and homatropine were similarly hydrolyzed at 25C while apoatropine remained unchanged. Some enamines (161 and 162) of tropinone were prepared by treating this ketone with cyclic secondary amines such as piperidine and morpholine in the presence of an organic solvent, p-toluenesulfonic acid, and a water-absorbing agent such as zeolite (121).
CH,N CH3N
161
162
A tropanyl Grignard reagent was prepared (122) by heating 3achlorotropane with magnesium turnings in refluxing THF for 24 hours (the p-isomer failed to react with magnesium under similar conditions). This reagent reacted with 2-(trifluoromethyl)thioxanthen-9-one to form 2-trifluoromethyl-9-(3-tropanyl)thioxanthen-9-01 (163). This alcohol was dehydrated and then reduced to form the 9-tropanyl derivative 164.
HO R
CFS
q
H R
CF,
163
R =
164
In accord with earlier work on tropinone (98a), photooxidation of tropan-3a-01, tropan-38-01, and deoxyscopoline (165) produced N demethylated and N-formylated products. Scopoline (166), however, formed tetrahydrooxazine (167) along with the N-formylated derivative.
165
166
167
132
ROBERT L. CLARKE
Secondary amines and cyclization products were postulated as forming via an immonium ion (98b). When tropan-3a-01 is irradiated in the presence of methylene blue and oxygen, it is transformed into a mixture of N-formylnortropan-3a-01 (60%), nortropan-3a-01 ( 5 % ) and tropan3a-01N-oxide (5y0). If, under the same conditions, sodium pyruvate is added, nortropan-3a-01 is formed in 65% yield with no N-formylated product observed (123).Again there was evidence of immonium ion intermediates. Functionalization of carbon-6 has been accomplished by cyclization of a nortropine (168, R = Ac or COOEt, R = H) to give a deoxynorscopoline (169, R = Ac or COOEt). Treatment of tropine N-oxide with acetic anhydride produced 0,N-diacetylnortropine (168,R = R = Ac).
J 3 R 4 5 ,
168
169
N 170 J !
Partial hydrolysis (KOH/MeOH)gave the 3a-01(168,R = Ac, R = H), which was treated with lead tetraacetate to form N-acetyldeoxynorscopoline (169, R = Ac). Removal of the acetyl group and Nmethylation then gave deoxyscopoline (169, R = CH,). Treatment of urethane 168 (R = COOEt, R = H) with Iead tetraacetate followed by LAH gave deoxyscopoline directly. Photolysis of the urethane nitrite 168 (R = COOEt, R = NO) gave the oximinonortropine 170 (89). Another study aimed at functionalization of the ethylene bridge explored the reaction of lead tetraacetate and iodine on tropine. Two main groups of products were formed in essentially equimolar quantities. One group consisted of a mixture of two iodo-acetoxytropanones 170A and 170B accompanied by small amounts of tropinone. The second group comprised a mixture of four dimers, 170C, 170D, 170E, and 170F, each containing two tropine moieties connected by a carbonyloxy group. Several reactions were run in characterizing the products (124).
170A
170B
2.
0
TROPANE ALKALOIDS
133
0
1 I
II
N CH3 I
\I
I70C
OH
N R IK O 2 9
170D,R = CH, 170E, R = COCH, 170F,R = CHO
Hydroboration of tropidine (171) with oxidative work-up gave a 68% yield of tropanols with a ratio of 43: 3: 50: 3 2a: 2/3: 3a: 3p. Principal attack of the double bond from the a-face presumably resulted from blockage of the p-face by an amine-borane complex. With a phenyl group on carbon-3, only a-01s were isolated, 3/3-phenyltropan-2a-01(172) being
171
172
produced in threefold greater amount than the 3a-01. Substituents on the aromatic ring modified this ratio (125). Oxidation of the 2a-01 (172)to 3p-phenyltropan-%one could not be accomplished with the usual oxidizing agents, so it was treated with ethyl chloroformate, and the resulting urethane was oxidized with Jones reagent to produce 173. Reduction of 173 with LAH then gave 3/3EtOCON
4 J k b
173
2qQ
174
phenyltropan-2p-o1(174), which was wanted for biological testing (126). Some 2a-01 was also formed in this reduction. Variation of the substituent on the nitrogen of norscopolamine and noraposcopolamine has been accomplished through reaction of these
134
ROBERT L. CLARKE
nor-bases with alkyl monohalides and dihalides, isocyanates and isothiocyanates, and epoxides. N-carbamoylnorscopolamine and N carbamoyl-O-acetylnorscopolamine were synthesized from the corresponding N-cyano compounds (127). A similar series of reactions was run on norpsicaine (175) and neonorpsicaine (176).These secondary amines were treated with alkyl
J~-- ~-cOo~ J)x

175 176
COOCBH,
OCOPh
monohalides and dihalides ( l 2 8 ) , monoisocyanates, 1 ,g-hexandiyldiisocyanates, acrylonitrile and ethyl acrylate (129),and CTHJ (55). Benzoyl chloride reacts with tropine (177)to form dibenzylidenetropinone (178).At the time of its discovery this surprising reaction, which involves an oxidation, was postulated as proceeding via a hydride shift (130). A reinvestigation employingdeuterium labeling has confirmed this mechanism (132).As outlined in Scheme 1, the deuterium at C-3 is
PhCOCl
4 N NaQH
,D
OH
177
Ph
Ph
178
SCHEME 1
135
transferred to form deuterated benzaldehyde, two molecules of which then attack a single tropinone. The structure of the deuterated product was confkmed by NMR and mass spectroscopy. Tropinone reacted with the lithium salt of o-lithium-benzoic acid (178A) a t - 78C to form a spiro tropane (178B) in 58% yield. Reduction
II
178A
178B
of this lactone (178B) with LAH-BF, afforded spiro ether 178C in 81% yield. Reaction of tropinone with o-lithium-phenol gave the phenolic alcohol 178D in 20% yield ( 1 3 1 ~ ) .
178C
178D
The radiation yield from the 6oCo irradiation of dilute aqueous atropine sulfate and scopolamine hydrobromide was independent of alkaloid concentration but decreased with increasing radiation dose. The biological activity of irradiated solutions correlated with radiolytic decomposition. Atropine yielded tropine and tropic acid, indicating radiation-induced ester cleavage (1 32). Cocaines labeled with deuterium on the aromatic ring a t position 4 and (separately) at positions 3 and 5 (179) were prepared by reductive dehalogenation (NaBD,-PdC1,) of the corresponding chlorobenzoates. Hydrolysis of the methyl ester functions then provided the correspondingly labeled benzoylecgonines (180)(133).
136
ROBERT L. CLARKE
V. Biosynthesis
A. TROPANE MOIETY
Substantial evidence has accumulated to support Scheme 2 as the route for bioconversion of ornithine to hyoscyamine. A detailed review of this evidence appeared in The Alkaloids (London) in 1971 (134). Only a few key experiments will be reported here. Incorporation of [Z-14C, 6-15N]ornithine(181), [1,4-14C,]putrescine, and [4-3H]N-methylputrescine (182)into hyoscyamine has been observed. Evidence indicated that these precursors were confined almost entirely to the pyrrolidine ring (135). N-Methylputrescine (182) was a much better precursor for hyoscyamine in Scopolia lurida Dun. than either putrescine or ornithine (135). Whereas 6-N[3H]-methylornithine served as a good precursor for hyoscyamine with a major portion of the radioactivity confined t o the N-methyl group, ~t-N-[~H]-methylornithine showed only minute nonspecific incorporation (136). When this experiment was done with 6-N-[14C]-methyl-[2-14C]-ornithine, degradation experiments indicated that all of the activity was located in the tropine base a t the bridgehead carbon C-1 [having the (R)-configuration]and on the N-methyl group (137). dZ-N-[14C]Methyl[2-14C]hygrine was incorporated into hyoscyamine by D . stramonium L. (138). A slightly different sequence has been proposed wherein ornithine is
2.
TROPANE ALKALOIDS
137
181
Ornithine
182
I
CH,
CHB Hygrine
0
Tropinone
183
SCHEME 2
said to be converted to aminobutyraldehyde, which then gives y(N-methylamino)-butyraldehyde (139). A further different sequence postulates that hygrine-a-carboxylic acid is the key intermediate in tropane synthesis. Radioactive hygrine showed a lower incorporation into tropane alkaloids than did [2-14C]-ornithine.The same study showed that [1-l4C]-acetate gave rise to labeling of the carboxyl group of ecgonine (140). Another proposal for tropine biosynthesis is an outgrowth of studies with tissue cultures. A cell suspension culture of Datura ferrox L., when supplied with dl-[2-l4C]ornithine, yielded radioactive a-keto-Baminovaleric acid (184), among other products. However, none of the tropane alkaloids produced was radioactive. It was proposed that this in vitro cell culture lacks the enzyme that catalyzed the reaction between A1-pyrroline-2-carboxylic acid (185) and acetoacetylcoenzyme A. This condensation product can ultimately yield hygrine and then tropine, as illustrated in Scheme 3 (141). Finally, there is the observation that [1,4-14C,]succinic acid is incorporated in Datura species, the molecule becoming carbons 1, 5 , 6, and 7 of the tropane structure. [1,3-14C,]acetone and [14C]methylaminewere also utilized (142). An enzyme (atropinase) is believed to play an important role in the biosynthesis of tropane alkaloids (142a).
138
ROBERT L. CLARKE
0
COOH
COOH
CS-COA
It
184
185
tropinone
-L L > O - c k - o
COOH CS-COA Hygrine
II
SCHEME 3
B. CARBOXYLIC ACIDMOIETY
A critical review of the biosynthesis of tropic acid appeared in Biosynthesis (143) in 1973. Feeding experiments using variously labeled phenylalanine have shown that all of its carbon atoms are incorporated into tropic acid but that the carboxyl group migrates fiom C-2 to C-3 in the process (Eq. 13) (143).The intramolecular character of thisrearrangement was demonstrated by feeding phenylalanine containing 13C a t
Pheny lalanine
Tropic acid
positions 1 and 3 to Dutura innoxiu. Movement of the two labeled carbons to contiguous locations resulted in the appearance of satellite peaks (NMR) due to spin-spin coupling, symmetrically located about the corresponding singlet peaks. If the rearrangement had been intermolecular, endogenous unlabeled phenylalanine would have diluted this effect beyond visibility (144). Although it had been shown earlier that cinnamic acid, a metabolite of phenylalanine, failed to serve as a precursor of tropic acid ( l 4 5 ) ,there was the possibility that rearrangement might occur after esterification of tropine with an acid derived from phenylalanine. Therefore, [2-14C]-
2.
TROPANE ALKALOIDS
139
cinnamoyl N[14C]methyltropine was fed to D . stramonium. Although activity was found in both hyoscyamine and scopolamine, all of it was located in the N-methyl groups, indicating that hydrolysis of the ester had occurred with no use of the cinnamic acid in biosynthesis of tropic acid (146).Similarly, [2-14C]cinnamicacid was not incorporated into the alkaloids of D . innoxia plants when fed via the roots. I n this same study, (dZ)-[2-14C]phenyllacticacid served as a better precursor than [2-14C]phenylalanine for tropic acid in hyoscine and hyoscyamine and for atropic acid in apohyoscine. Phenylalanine served as an effective precursor for the phenyllactic acid moiety of littorine ( 1 4 6 ~ ) . I n contrast with the above observations, a feeding of [2-14C]cinnamic acid to D. innoxia through the stem via the wick method has recently shown specific incorporation into the tropic acid moiety of atropine. The tropic acid was labeled at C-3. This 0.0S70 incorporation of [2-14C]cinnamic acid into atropine compares favorably with that reported by others for the incorporation of radioactive phenylalanine into this alkaloid (147). Biosynthetic studies of hyoscyamine in callus tissue and intact plants of A . belladonna showed that addition of phenylpyruvate produced a significant increase in alkaloid production. Phenylalanine had little effect and cinnamic acid inhibited both growth and alkaloid production. I n a tagged precursor study using leaf discs, tyrosine showed less incorporation than did phenylalanine ( 1 4 7 ~ ) . Whereas considerable attention has been given to the formation of tropic acid from phenylalanine, little attention has been devoted to its biosynthesis from phenylacetic acid (148) and from tryptophan (149) following these early studies. A criticism leveled at the proposed route from tryptophan (149) (see Scheme 4) was that the [3-14C]tryptophan
R--CH,-CH-COOH
[3-"C] Tryptophan R =
NHz
---
R--EH~--C-COOH
I1
+ R-~H~COOH +
REHO
(J-H
COOH
- *COOH
Tropic acid
SCHEME 4
140
ROBERT L. CLARKE
used for the study did not show that tryptophan was able to furnish the entire carbon skeleton of tropic acid. Recently ( 1 5 4 , [benzene ring U-14C]tryptophan and [2-ind01yl-~~C]tryptophan were converted t o tropic acid by D . innoxia roots. The bulk (My0)of the benzene labeling appeared in the phenyl ring of the tropic acid and 61% of the 2-indolyl14C label appeared at C-3 in the tropic acid, thus substantiating the earlier hypothesis (149).[1-14C]Phenylalanine, [l-14C]phenylaceticacid, [3J4C]serine, and [14C]formicacid were also utilized. Dually labeled littorine, 3a-([l-14C]-2-hydroxy-3-phenylpropionyl0xy)[3-~H]tropane,was fed to D . stramonium which then yielded radioactive hyoscyamine. Both the tropine and the phenyllactic acid halves of the molecule were incorporated into the hyoscyamine moiety, but the ratio of labeled atoms was so drastically changed that there was indication that the ester was hydrolyzed to tropine and phenyllactic acid, the latter undergoing rearrangement to tropic acid before being reesterified by tropine (146). The origin of the phenyllactic acid moiety of littorine in D . sanguinea is phenylalanine. A specific incorporation of [ 1J4C]- and [3-14C]phenylalanine was observed into carbons 1 and 3, respectively, of the side chain of the phenyllactic acid portion of littorine. The fact that phenylalanine appears to be a better precursor for littorine than for hyoscyamine and scopolamine suggests that phenylalanine is more readily converted to phenyllactic acid than to tropic acid (151). Whereas tropic acid and 3-phenyllactic acid are formed from phenylalanine, the tiglic acid of tigloidine and related esters and the 2-methylbutanoic acid of 6/3-( 2-methylbutanoyloxy)tropan-3cr-olhave their origin in (8)-isoleucine.(8)-Isoleucine was first shown to be a precursor for the tigloyl moiety of tropine tiglate (186), tropane-3a,6/3-diol ditiglate (187), meteloidine (188), and tropane-3a,6/3,7/3-triol 3,6ditiglate (189) in D . innoxia and in D . meteloides D. C. ex Dunal in 1966 (152). The next year these findings were substantiated when the
0 -0-c
Tig =
II
/
\
CH3
Tig 186 R ' = H, Ra = H ' = Tig, R1 = H 187 R ' = OH, Ra = OH 188 R 189 R1 = Tig, Ra = OH
,c=c
CHa
2.
TROPANE ALKALOIDS
141
radioactivity of [2-14C](S )-isoleucine was specifically incorporated into the ester carbonyl of meteloidine (188) in D . meteloides (153).The tiglic acid moiety of tigloidine (pseudotropine tiglate) and tropine tiglate from Physalis peruviana L. is also derived from (S)-isoleucine (154). The intermediacy of 2-methylbutanoic acid in this conversion was indicated when dl-[l-14C]-2-methylbutanoicacid was fed t o D . innoxia and the root alkaloids tropane-3a,6/3-diol ditiglate (187) and tropane 3a76/3,7/3-triol 3,6-ditiglate (189) were isolated. In each case, the radioactivity was located in the ester carbonyl group (155).The same sort of incorporation was observed when dl-[l-14C]2-methylbutanoic acid was fed to D . meteloides, radioactive meteloidine being isolated. It was predicted that it is the (S)-2-methylbutanoic acid which is the actual precursor of the tiglic acid since it is the ( S )form of isoleucine that starts the sequence (156). The tiglic acid observed in these alkaloids apparently is formed by a direct dehydrogenation of 2-methylbutanoic acid, although nothing is known of the stereochemistry of elimination. In order to discount the possibility that the dehydrogenation first gave angelic acid which then isomerized, [l-14C]angelicacid was fed to D . innolcia plants. There was no incorporation, thus clearly indicating that angelic acid is not a precursor to tiglic acid. Tiglic acid was incorporated under these same conditions (157). 2-Methylbutanoic acid, which was an intermediate in the conversions just described, appears as an end product in tropane-3a76/3-&o1 6-(2methylbutanoate) from D . ceratocaula. The origin of this acid was demonstrated by feeding [U-l*C](S )-isoleucine(22). Leucine and valine appear able to act as precursors of the isovaleryl and senecioyl moieties of the tropane alkaloids, although such a conversion may not occur in a normal plant. Radioactivity from [U-14C](S)-leucine and [U-l*C](S)-valine was incorporated into the acid portions of tropine senecioate and isovalerate, tropane-3,6-diol disenecioate, and diisovalerate, and into tropane-3,6,7-triol 3-senecioate, 3-isovalerate, 3,6-disenecioate, and 3,6-diisovalerate. The species fed were D . sanguinea and D . stramonium (158).
C. TRANSFORMATIONS
The principal pathways for the biotransformation of cocaine in men and in animals are N-demethylation and deesterification. Monkeys injected intraperitoneally with cocaine were shown to develop identifiable levels of norcocaine in brain tissue (extraction, gas chromatography
142
ROBERT L. CLARKE
and mass spectrum). This metabolite is about as active as cocaine in inhibiting 3H-norepinephrine uptake by synaptosomes prepared from rat brain (159). It has been observed that ditiglate esters of tropane-3a,6f15-diol and tropane-3a,6fl,7/3-triol exist in the roots of Datura species, but that only monotiglate esters are found in the leaves. The isolation of some ditiglate esters in transpiration streams led to the hypothesis that such diesters are metabolized to monoesters in the leaves. The idea was substantiated when tropane-3a,6/3-diol ditiglate was fed to D . innoxia and D. cornigera Hook. leaves where it underwent hydrolysis to yield the 3-tiglate, the 6-tiglate, and tropane-3a,6/3-diol (160). A subsequent substantiation of the process was effected using solanaceous species that normally do not contain tiglate esters. Experiments with tropane-%a,6/3-diol ditiglate in Atropa belladonna L. and Lywpersicum esculentum (L.) Mill. and with tropane-3a,6/3-dioldisenecioate in L. esculentum and Datura ferox indicated their conversion to monoesters (161). [3/3-3H,N-14C-methyl]tropinewas fed to D. meteloides, giving rise to radioactive meteloidine, scopolamine, hyoscyamine, and tropane30,6/3,7/3-triol 3,6-ditiglate. These products had essentially the same 3Hj'4C ratio as in the administered tropine. Degradation of the meteloidine established that all of its 3H was located at C-3 and all of the 14C w a s on the N-methyl group, indicating that tropine is a direct precursor of teloidine (162). Feeding of [N-14C-methyl-6,8,7/3-3H,ltropine to D. inmoxia and D. meteloides produced hyoscyamine with a 3H/14Cratio essentially t h e same as that of the administered tropine. However, the meteloidine and scopolamine formed retained only small amounts of tritium. Thus, the dihydroxylation of the tropine moiety proceeds with retention of configuration. If previous work on the biosynthesis of scopolamineis accepted, the present results indicate that a cis-dehydration is involved in the formation of 6,7-dehydrohyoscyamine from 6bhydroxyhyoscyamine (16%). A mutual interconversion between scopolamine and hyoscyamine has been ascertained during incubation of shoots and roots of D. innoxia. When [N-14C-methyl]scopolamine was added, radioactive hyoscyamine could be isolated. When [N-14C-methyl]hyoscyamine was added, labeled scopolamine was formed. 6-Hydroxyhyoscyamine was an iutermediary (163). In studies concerning the biosynthesis of tropane-$a,6/3-diol,tropane3a,6/3,7jS-triol, and their tigIate esters it has been shown by feeding experiments with [14CO][N-14Me]3a-tigloyloxytropaneand [l4C0] [P4Me]valtropine that neither precursor is incorporated intact to gipe diesters. Extensive reversible hydrolysis occurs ( 1 6 3 ~ ) .
2.
TROPANE ALKALOIDS
143
A different approach to this problem involved the determination of whether the entering tigloyl groups labeled equally the 3a and 6p positions in ditigloyl esters. Two different mechanisms appeared to be involved when [1-14C]tiglicacid was fed to D. meteloides. 3a,6p-Ditigloyloxytropane contained roughly equal radioactivity a t positions 3 and 6. This suggested hydroxylation of tropine followed by simultaneous esterification. In contrast, 3a,6/3-ditigloyloxytropan-7~-01 had only 9% of the label at position 3. It may well have been formed by hydroxylation of 3a-tigloyloxytropane (163b). A third study by the same group resorted to feeding [N-14Me]tropine, a known precursor that does not lose its label, alongside postulated intermediates in each of the biosynthetic schemes to act as competitive inhibitors. The results favored two separate routes for the biosynthesis of the tigloyl esters of tropane-3a,6/3-diol and tropane-3a,6p,7/3-triol (163c):
(a)Either
+ 3a,6fi-ditigloyloxytropane tropine + tropane-3a,6fi-diol
or more probably,
tropine + 3a-tigloyloxytropane+ 6fi-hydroxy-3a-tigloxytropane -.+ 3a,6fi-ditigloyloxytropane (b) + tropine + 3a-tigloyloxytropane 7fi-hydroxy-3a-tigloyloxytropane 6fi,7fi-dihydroxy3a-ditigloyloxytropane 3a,6fi-ditigloyloxytropane-7~-ol
--f --f
An independent study of this same question involved feeding a 1 :1 mixture of 3a[l-14C]tigloyloxytropaneand 3a-tigloylo~y[3/3-~H]tropane to D. innoxia. The 7/3-hydroxy-3a,6/3-ditigloyloxytropane so formed contained the same 3H/14Cratio as that fed. From this result it seems probable that hydroxylation a t C-6 and C-7 occurs on the preformed %a-tigloyl ester (163d). In another study of hyoscyamine and scopolamine, the latter was infiltrated into shoots of intact Solandra grandiflra Sw. In addition to the normal alkaloids to be found there, dl-scopolamine,aposcopolamine, dl-norscopolamine, and oscine were isolated. It was inferred that the new metabolites arose from scopolamine and that racemization of the optically active bases is in keeping with the normal occurrence of atropine and noratropine in the plant. In another experiment [GJ4C]hyoscyamine and unlabeled hyoscyamine were infiltered into alkaloidfree scions of s. grandiflra grafted onto tomato stocks. Atropine, noratropine, and tropine were isolated (164). [2-14C]Acetate, [3H]atropine, and [N-14C-methyl]tigloidine were applied to seedlings and cut off young stem ends of D. innoxia and the disposition points were determined by autoradiograms. The tigloidine was not transformed into scopolamine in 3 days. However, within 1 day
144
ROBERT L. CLARKE
radioactivity appeared in 6-hydroxyhyoscyamine and tropane-3a,6/lB,7/ltrio1 3,6-ditiglate. On the second day it was detected in meteloidine (165). Two other metabolic studies in animals have been reported. The metabolism in rats of methylscopolammonium methylsulfate, a quaternary developed as an anticholinergic agent, was investigated. The major pathway apparently involved introduction of a hydroxy or methoxy group in the para position of the benzene ring. There was also indication of glucuronide formation (166).Injection of [N-14C-methyl]scopolammonium methylsulfate and two related salts into rats (intravenously) resulted in localization of the radioactivity in the lysosomes of the light mitochondria1 fraction of the liver (167).
D. TISSUE CULTURESTUDIES It was hoped that tissue cultures of alkaloid-producing plants would be an ideal system for studying biosynthetic routes since these systems could be so well controlled. Unfortunately, these systems produce much poorer yields of alkaloids than the intact plants and work of this type has proved disappointing. Cell cultures of Datura innoxia have developed shoots that in a different medium have developed into complete plants. During root differentiation and plant development, scopolamine synthesis begins and there is progressive increase in alkaloid content. The majority of plants develop a normal pattern of alkaloid content (168). The alkaloid spectrum of tissue cultures of D. metel, D . stramonium var. stramonium, and D . stramonium var. tatula was found to differ considerably from that of intact plants. Neither hyoscyamine nor scopolamine was detected in these tissue cultures. Hyoscyamine, added to the cultures, was steadily consumed over a 14-day period but no scopolamine developed, a transformation that occurs in intact plants (169).In contrast to the results of that study, calius tissue cultures of D . myoporoides leaves contained at least five alkaloids which corresponded by tlc to those found in leaves and roots of intact plants. The main alkaloids identified were scopolamine, Callus . cultures from leaves of anther valtropine and atropine ( 1 6 9 ~ ) regenerates of D . ferox, D . inermis, D . meteloides and D. tatula were analyzed for their ability to produce tropane alkaloids and t o excrete these into the culture fluid (169b).Optimum release of alkaloids into the broth of cultures of D . innoxia and S. stramonijolia occurred a t 25" and 15 atmospheres of sucrose osmotic pressure ( 1 6 9 ~ )Hyoscyamine . production by anther cell suspensions of D . metel was highest when the Murashige-Skoog medium was used (169d).
2.
TROPANE ALKALOIDS
145
In excised root cultures of D. innoxia, the addition of tritiumlabeled atropine did not affect the normal synthesis of atropine and scopolamine. Part of the exogenous atropine was converted to scopolamine. The relation between unchanged and converted substrate indicated a regulation of the enzyme required for this conversion (170). Formation of tropoyl esters in cultures of D. innoxia stem callus was stimulated by dl-tropic acid, phenylpyruvate, or tropine but was little affected by (S)-phenylalanine or (8 )-ornithine. Acetyltropine was formed in large quantity by cultured cells when tropine was supplied to cultures of D. innoxia and D. tatula L. (171).Another study also observed evidence for the presence of enzymes for tropine acetylation in Datura cultures (172). A . belladonna, S. lurida, and H . niger cultures did not esterify tropine ( 1 7 3 ~ ) . A three- to sixfold increase in atropine production resulted from addition of (,Y)-phenylalanine or (S)-tyrosine to tissue cultures of D. metel (173). Addition of dl-[l-14C]tyrosine to this same kind of culture yielded radioactive atropine (174). The shapes of cells in tissue cultures of D. innozia depended on growth conditions, while their size depended upon origin. Biomass formation was faster in calluses from leaves and petioles than in those from stem, root, or seed. Amino acids, such as ornithine, phenylalanine, serine, aspartic acid, methionine, and glycine, caused an increase in alkaloid synthesis by the medium (175). In contrast, another report states that addition of (S)-ornithine, (#)-proline, or (S)-hydroxyproline caused no appreciable synthesis of tropane derivatives in D. metel stem and root cultures and in D. stramonium var. tatula root cultures. These cultures do not produce tropane alkaloids without addition of some sort of precursor, however. Addition of tropine caused production of a large quantity of hyoscyamine ( 176). In order to maximize the alkaloid formation in tissue cultures of D. innoxia seeds and Scopolia stramonifolia roots, a two-factor dispersion analysis was applied. Studied were the method of sterilization of the medium, the number of transplantations, the revolution speed of the cultures, and the volume of the nutrient medium (177). In tissue cultures of callus cells of S. stramonifolia, the total alkaloid content was highest after 3-month cultivation (0.1157J. Additives such as tryptophan and ATP caused higher proportions of scopolamine and hyoscyamine t o form ( 1 7 7 ~ ) . Suspension and static cultures of tissues of D. innoxia and S. stramonifolia exhibited similar annual rhythms, manifested in uneven growth and production of alkaloids. Greatest productivity of alkaloids occurred in spring; least occurred in winter. There appeared to be a reciprocal
146
ROBERT L. CLARKE
relationship between growth and alkaloid formation. Diurnal rhythms were expressed in the mitotic activity and annual rhythms in the metabolism of nitrogen, principally in proteins and amino acids (1?7b). A relationship has been demonstrated between protein synthesis and alkaloid synthesis in root cultures of D. stramonium var. tatula (178). Studies in several nutrient media were conducted on root explants of D. stramoniurn var. tatula, D. stramonium var. stramonium, D. stramonium var. chalybea, D. innoxia and D. ferox. D. stramonium var. stramonium grew best in Torreys medium without vitamins. Production of atropine and scopolamine was confirmed by chromatography (178a). The possibility of replacing the production of hyoscyamine and scopolamine from Scopolia himalaiensis root callus tissues on agar or from whole plants by production from liquid suspension cultures was explored. The process has the advantage of ease of nutrient addition and simplified product isolation. The results were promising (179).Aeration of a suspension culture of D. innoxia stimulated tissue growth and alkaloid productivity. While the content of alkaloids in callus tissue increased under these conditions of intensified oxygen supply, excretion into the medium decreased (179a).In tissue cultures of Scopolia species leaves the presence of tropane alkaloid precursors is said to lower the total yield of alkaloids (180). The effect of some aminoacid precursors on the growth and alkaloid-production of callus tissue cultures of severalScopolia species was studied. Tryptophan, phenylalanine, glutamic acid, proline, ATP, and various combinations of these were added. Tryptophan, followed by glutamic acid and ATP, showed strong induction of hyoscyamine and scopolamine formation (181). Addition of atropine sulfate to D. innoxia cultures stimulated growth and biosynthesis of hyoscyamine and scopolamine (181a).
E. MISCELLANEOUS BIOSYNTHESES
Exposure of D. stramonium plants to l4CO; resulted in incorporation of radioactivity into all the alkaloids present. The ratio of radioactivity of hyoscyamine to that of scopolamine was much higher in the roots than in the foliage. This activity was present in both the acidic and basic moieties of these alkaloids (182). Atropa belladonna that had been grown to maturity in aqueous nutrient solution died within a week when transplanted into 1 0 0 ~ o D,O. Plants lived only about three weeks in 757, D,O but survived in 50 and 60% D,O. Alkaloid production was drastically reduced in these survivors (183).
2.
TROPANE ALKALOIDS
147
Autoradiographic studies of histological structures of various freeze-dried animal organs permitted the location of atropine and its metabolites in the animal. Atropine and atropine 9-glucuronide were found in largest amounts followed by 4-hydroxyatropine and its glucuronide. Tropine and tropic acid were found in small amount. There was a direct relationship between these concentrations and the pharmacological activity (1 84).
M. Biologid Activity
Only a selected few biological activities will be reported here, those being of unusual degree or involving tropanes with other than stereotypical structures. The vast literature on biological properties of cocaine and the various tropan-3-01 esters will be omitted. One of the first properties observed about cocaine was its ability to produce numbness of the tongue. When Willstltter prepared a position isomer of cocaine in 1896 called a-cocaine (190), he observed bhat it produced no local anesthetic action on the tongue (86).I n 1955 it was demonstrated that a-cocaine was actually one-third to one-eighth as strong a local anesthetic as cocaine in an intradermal infusion test (185).
J&q0lPh
COOCHB
190
J k $
OCOPh COOCH,
191
Two years later it was proved that the isomer prepared by Willstltter had the carbomethoxy group in the endo configuration as drawn (190) (87). Recently (1975) ,!?-cocaine (191) was prepared (see Section IV, D). It proved also to have no local anesthetic action on the tongue but was one-third as active as cocaine in the intradermal wheal test (88).Thus, the two isomers have similar local anesthetic activities. ,!?-Cocainedoes not have the stimulative action shown by cocaine (186).a-Cocaine has not been studied in this respect. Several further modifications of cocaine have been studied pharmacologically. The preparation of these compounds is described in Section IV, D. A Lreverseester of cocaine (192) was found to be devoid of
148
ROBERT L. CLARKE
stimulative action (83).However, some benzaldehyde acetal derivatives (193) of the intermediate diol used in the preparation of this reverse ester proved to be stimulants (84).Those isomers in the group which
0
CH,N
i\
O---CCHB
II
CH,N
I\
192
193
had the aromatic ring in the a configuration showed activity in the reserpine-induced eyelid ptosis test. Included in this same study were the benzaldehyde acetals of ecgoninol and pseudoecgoninol (194), only the former of which was active. The latter was the most lethal of all the compounds tested.
dl-3/?-Phenyltropan-2/?-01 (195) has about the same activity as does cocaine in the reserpine-induced ptosis test but is more active as a locomotor stimulant. The activity appears to reside in only the 1enantiomer. Curiously, the racemate appears to be more active than the active enantiomer alone. The ethylene bridge of the tropane system is required for activity. Acetylation of 195 produces a decrease i n activity (126). In contrast to the above observations, it is the acetate of the 2a-01 (196) that is a strong stimulant. The alcohol produces questionable depression (126).
195
196
2.
TROPANE ALKALOIDS
149
The most dramatic change in the cocaine activity profile resulted from elimination of the elements of CO, from cocaine, i.e., attachment of the benzene ring directly to carbon-3. The compound of structure 197 (R = p-F) is about 65 times as active as cocaine as a locomotor
197
198
CH3?,
&
COOCH,
199
stimulant, about 20 times more active in inhibition of tritiated norepinephrine (NE-3H)uptake in mouse heart, 25 times more active in inhibition of NE-3Huptake in rat brain, 5 times as active in preventing reserpine-induced eyelid ptosis and 20 times more active in reversing this ptosis, one-tenth as strong a local anesthetic, and about one-fourth as toxic as cocaine intravenously. The oral therapeutic ratio as a locomotor stimulant is about 300 (85). This compound (subcutaneously) was able to cause a 5970 inhibition of NE-3H uptake in rat brain at a 5.3 mg/kg dose as compared to a 6-87, inhibition (subcutaneously)by desmethylimipramine a t 20 and 40 mg/kg. The latter compound, one of the most active NE-3H uptake inhibitors known, apparently is not very effective in penetrating the blood-brain barrier (187). The sensitivity of 197 (R = p - F ) to structural change is demonstrated by the fact that removal of the ethylene bridge (198) or epimerization a t carbon-2 (199) destroys the central nervous system stimulation. It is the levorotatory enantiomer (with the cocaine absolute configuration) that is active. The dextro enantiomer actually produces a slight depression (85). One of the metabolites of cocaine is norcocaine. It has been found t o be about as active as cocaine in inhibiting uptake of NE-3H by synaptosomes prepared from rat brain. Other metabolites were found to be relatively inactive (159).
150
ROBERT L. CLARKE
Central nervous system stimulant activity has been reported for another type of tropane ester, namely ethyl A3*a-tropeneacetate (200), prepared by a Wittig reaction on tropinone (188).A somewhat similar stimulant (201)was prepared from tropinone via treatment with a reagent prepared from P$P, t-BuOK, and trichloromethane (189).
200
201
The fact that a synthetic homolog of batrachotoxin containing a 2,4,5-trimethylpyrrole-3-carboxylate was twice as active as batrachotoxin prompted the esterification of some hydroxylated alkaloids with this acid. Scopoline 2,4,5-trimethylpyrrole-3-carboxylate (202) was 20y0more active than codeine as an analgesic in the hot plate assay.
202
It had no effect on release of tritiated norepinephrine from heart tissue

(190). Earlier, the troprtneanalog (203) of meperidine (204) was found to have about the same activity as meperidine as a narcotic analgesic (191). Recently, the epimeric form (205) of this tropane analog was prepared
k
203
CH3N
COOEt
c H 3 N %
COOEt
Akh
205
COOEt
204
2. TROPANE
ALKALOIDS
151
(45) and found to be about one-third to one-fourth as active as the earlier epimer. The difference in activity is not great and could be due to differences in rate of passage into the brain. It suggests that the analgesic activity in meperidine-like compounds is not very sensitive to the conformation of the phenyl group. These results tend to support the findings of other workers with regard to phenyl group configuration (192, 193). Since 203, 204, and 205 all have equal local anesthetic activity, the study also shows that there is little conformational requirement for local anesthetic activity. Of nine tropane esters studied only tigloidine (206) and 3/?-senecioyloxytropane (207) significantly reduced the hypothermia induced by tremorine. None of the esters reduced the tremors caused by this agent. Only dZ-3,6-bis(2-methylbutyryloxy)tropane reduced the salivation. Tigloidine has been shown to be beneficial in the treatment of parkinsonism like atropine, but without many of the undesirable side effects of the latter drug. The antihypothermic effects of ester 207 suggest
No
206
R =
\C-c CH/
-C
/H
\
CH3
207
-c\ c=c /CH3 \

H/
No
CH,
a possible use of this agent in the symptomatic treatment of parkinsonism (194). A patent claims that some N-(ethoxycarbony1)nortropinone derivatives are also useful in the treatment of Parkinson's disease (195). Some 3-phenoxynortropanes of structure 208 where R = NH,, CH,NH, (CH,),N, or C,H,NH and R' = m-CF, or p-CF, have shown anticonvulsant activity. While none of these compounds is quite as active as diphenylhydantoin in suppressing electroshock-induced convulsions, several had protective ED,, values against pentylenetetrazole lower than that of ethosuximide. Both 3a- and 3fi-isomers were included in the study (106).The preparation of these compounds is described in Section IV, G .
152
ROBERT L. CLARKE
208
209
3-Phenoxytropane (209) and six derivatives carrying substituents in the aromatic ring are reported to induce hypermotility, potentiate the action of norepinephrine and inhibit that of tyramine on blood pressure, and to antagonize some effects of tranquilizers. The unsubstituted phenyl derivative was the most active (196). Another broad study of tropanyl ethers showed indications of antidepressant and anticholinergic activities. fl-Phenoxytropane and /?-(p-chlorophenoxy)tropane seemed to be active enough antidepressants and antiparkinson agents to warrant clinical trials (105). 3a-Hydroxy-8-isopropyltropaniumbromide (dZ)-tropate (Ipratropiumbromide) (209A)has pronounced anticholinergic properties. As
O-C-CH-CH~OH
209A
an inhibitor of the secretion of free hydrochloric acid in the stomach, it is five times more effective than atropine. A whole issue of Arzneimittel Forschung is devoted to the synthesis, pharmacology, toxicology, and clinical trials of this compound ( 1 9 6 ~ ) .
S
210
2.
TROPANE ALKALOIDS
153
Duboisia myoporoides is used by New Caledonian natives as an antidote against ciguatera poisoning (196b). N-(Allylthiothiocarbony1)tropane(210) is reported to have herbicidal activity (192').
W. Plant Content
Since the thrust of this review is primarily chemical and biochemical and not botanical, a detailed discussion of new or repeat isolations of known tropane alkaloids from new or old sources will not be given. However, the literature search for this review has provided what is hoped are essentially all references to work of this nature in the period reviewed. It appeared useful at least to catalog these references here as resource material. They are organized alphabetically according to family, genus, and species.
Family Erythroxylaceae Erythroxylum momgynum Roxb. (26). E . Ellipticum R. Br. ex Benth. (27). E. coca vm. nOv0granaterwi.q (198). Family Euphorbiaceae Peripentadenia m r 8 i i (C. T. White) L. S. Smith (24). Family Proteaceae Agastachys d w a t a R. Br. ( 9 ) . Belkndena mntana R. Br. (7-9). Darlingka ferruginea J. F. Bailey (11). Darling& &rlingiana (F. Muell) L. A. S. Johnson (11). Knight& de-phnchei Vieill. ex Brogn. et Gria (12-14). Family Rhizophoraceae Brugukra 8exanghr (Lour.)Poir (15, 16). B. ezarktata Ding Hou (15, 16). Family Solanaceae (198a)-A broad study of some 19 genera and 54 species of Chinese solanaceous plants focused on the distribution of four tropane alkaloids, hyoscyamine, scopolamine, anisodamine (6-hydroxyatropine), and anisodine (a-hydroxyscopolamine) (211), and a nontropane alkaloid, cuscohygrine. These alkaloids were distributed in
Ph
311
154
ROBERT L. CLARKE
Solmeae, Hyoscyaminae, Mandragorinae, and Datureae but not in Nicandreae, Lyeiinae, Solaninae, and Cestreae. Przewalskk ahebbearei and P. tangutica were the best sources of these alkaloids (22b). AnthocerA litto7ea. Labill (199). A. tasmanica Hook. F. (200). A. Viacosa R. Br. (199). Atropa belladonnu L. 28, 147a, 201-205, 205a, 205b). Cyphnzandra betacea Sendtn. (206). Datura d b a Nees (206a). D. arborea L. (207). D. bernhardii Lundstrom (208). D. candida (Persoon) Safford (209). D. ceratocaula Jacq. (20, 21). D. Cornigera Hook. (209). D. discolor B e d . (210, 211). D. fastuosa L. (212). D. ferox L. (169b, 209, 209a). D. godronii (212a). D. inno& Miller (16, 19, 20, 169c, 207, 209, 212a, 213-218, 218-218e). D. leichardtii Muell ex Benth. (206a, 208, 209). D. Metel L. (207, 218-220, 218f, 218g). D. Metel var. fastuosa ( B e d . ) Dannert (209, 221, 221a). D. meteloides DC. ex Dun. (169b, 207, 209, 222). D. pruimsa Greenm. (223). D. sanguima R. and P. (22, 209, 224). D. stramnium L. (28, 201, 207-209, 213, 225-230, 230a). D. stramnium var. inermis (207). D. stramnium var. tatula (230b). D. stramnium x D. discolor (231). D. suaveolens H. and B. ex Willd. (18, 232). D. tatula L. (169b, 207). D. tatula var. immzis (169b, 207). Duboisia hopwodii F . (233). D. myoporoides R. Br. (169a, 196b, 234, 235, 235a). Hyoscyamw d b w L. (236). H. aurew L. (233). H . n@er L. (28, 201, 233). H. orientdis Bieb (236a). H. pu8illw L. (233). Mandragora autumnalis Bertol. (237). M . oficinarum L. ( v e d i s ) (28, 237). Nicotiana tabacum L. (238). Physali.9 alkekengi L. var. Franchetti Hort. (formerly bunyardii Makino) (29, 239). P. peruViana Mill. (30a, 154). Physochlaina a l a k E . Korot. (23, 30, 240, 241). P r m a k k i u shebbeurei (22b). P . tangutica Maxim. (22b). Salpichroa or-iginifolia (Lam.) Baillon [S. rhomboidea (Hook) Miers] (242). ScopolBa carnblica Jacq. (28, 206a, 225, 243-246). S. himalaiensis (179).
2.
TROPANE ALKALOIDS
155
S .japonica Maxim. (247, 247a).

S . Zurida Dun. (28, 225). S.pa&&ra (Dun.) Nakai (222, 247, 247a, 248). S . 8inesis Hemsl. (249, 250). S.atranzonifolia (169c, 251-254). S . tangut& Maxim. (225, 250, 251, 255-261, 261a). Solandra grandifira Sw. (262). S . guttata D. Don ex Lindley (262). S . hartwegii N. Br. (262). S. hirauta Dun. (262). S. muwantha Dun. (262).
VIII. Stereochemistry
The determination of molecular configuration using NMR, IR, and mass spectra has become so routine and such an incidental part of so many publications on tropane alkaloids that no attempt will be made to give overall references. I n a few cases where spectral studies are the principal thrust of the paper, a description will be given in this section. A novel approach to establishing configurations of molecules has involved attaching a chiral group to the nitrogen of some piperidones, tropan-3-ones, and pseudopelletierine systems (40). Where the chiral
Ph
3,
CH3
212
H c * 7 3
213
group was in closer proximity to the carbonyl (as in 212) the amplitude of the circular dichroism was enhanced over that of the isomer with the more distant chiral center (213).Both quaternary and tertiary chiral bases were studied. The conformer populations and their Cotton effect signs and amplitudes as predicted by the octant rule and theoretical considerations were confirmed by circular dichroic measurements. I3C NMR data are beginning to accumulate on tropanes. Shift assignments have been made for the carbons of tropane (263);nortropane (263); tropinone (263); tropinone ethylene ketal (263); tropine (263, 264) and its benzoate (263);atropine (61a, 263),it? methobromide
156
ROBERT L. CLARKE
(61a,263, 264), and other alkyl quaternaries (61a);pseudotropine (263) and its benzoate (263); tropidine (263); scopolamine (263, 264); scopolamine N-oxide (263);tropic acid (264); ethyl 3-phenyltropane-3(both carboxylate (both isomers) (45);and 3-benzoyl-3-phenyltropane isomers) (45). It is worthy of note that Wenkerts group (263) has assigned the 6 25.7 peak to carbons 6 and 7 of tropine and the 39.1 peak to carbons 2 and 4, whereas Maciels group (264)has made the reverse assignment. The latter group observed that atropine methobromide (214) showed methyl peaks a t 6 44.85 and 51.54. The N-methyl of atropine (known to
OTr
214
be equatorial) appeared at 39.57, in fair accord with the lower of the two values seen for the quaternary. X-ray work (265)has indicated an axial configuration for the N-methyl of scopolamine. The observed NMR shift for this carbon in scopolamine was S 53.42, in agreement with the other methyl peak location (6 51.54) found in atropine methobromide. With proper control studies, it might be possible to use 13C NMR effectively for structural assignments of tropane quaternaries. (The work following disagrees with these quaternary peak assignments.) This possibility of using 13C NMR has now been carefully explored for quaternaries carrying methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-octyl groups on the nitrogen. The shift differences between peaks for the two nonring carbons attached to the nitrogen and the peaks for the ring carbons at C-6/C-7, C-l/C-5, and C-2/C-4 have been correlated to show definite and distinct trends relatable to the orientation of the R groups on the nitrogen. This study allows configurational assignments for alkyl groups where one group is methyl but has not yet been extended to pairs of higher alkyl groups or to aralkyl substituents ( 6 1 ~ ) . The normal 13C population in molecules is so low that a specifically labeled 13C position stands out prominently in proton noise decoupled 13C NMR spectra. Likewise, adjacent 13C atoms give rise to satellite peaks (due to 13C-13C spin-spin coupling) that are symmetrically
2.
TROPANE ALKALOIDS
157
located about the singlet peaks. This phenomenon was utilized in establishing that phenylalanine (215) is a precursor of tropic acid (216) biosynthetically by intramolecular migration of the carboxyl group. No
215
Phenylelenine
216
Tropic acid
satellite peaks were visible in the dl-[l ,3-13C,]-phenylalanine fed to Datura innoxia, but they were plainly visible in the hyoscyamine and scopolamine isolated from the plant tissues (Eq. 14) (144). While on the subject of tropic acid, NMR studies (100 and 220 MHz) of it, its methyl ester, and the methyl ester acetate indicated a preference for the conformation where the phenyl and hydroxyl (or acetoxyl) groups were in anti positions to each other. Solvent and concentration effects upon the coupling were weak (266). Dipole moment, NMR and temperature-dependent NMR studies and qualitative considerations of van der Waals interactions provided data on the conformation of atropine (267).Since the primary focus was on the conformation of the ester function, acetyltropine, trimethylacetyltropine, benzoyltropine, hexahydrobenzoyltropine, and diphenylacetyltropine served as models. The structure wherein the C=O is cis to the tropane skeleton (218) appears to be the preferred conformation rather than the trans form (217). This brings the N to C=O distance to 4.5-5.0 A, which is close to that found for acetylcholine. An earlier study
,
0
C ,CHPhCH,OH
O\,@ CHPhCHaOH 218
II
217
(268) on tropine benzoate and pseudotropine benzoate had concluded that the former prefers the conformation 219 while the latter is an equilibrium mixture of 220 and 221. All of this work was directed toward gaining information on the characteristics of cholinergic receptors.
158
ROBERT L. CLARKE
O\,//O
Ph
219 220 121
The question of whether the lone electron pair or hydrogen assumes the equatorial position on nitrogen in piperidines and nortropanes has been the focal point of much controversy. A low temperature 13C-NMR study, directed toward a solution in the latter case, has revealed an almost equal population of axial and equatorial hydrogens (268,). The conformations of both phenyl tropan-3a-yl ether and p-chlorophenyl tropan-3a-yl ether as well as their 3b-epimerswere determined by analysis of IR, NMR, dipole moment, and K e n constant data. The piperidine ring of the tropane was found to be in a chair form and the N-methyl occupied an equatorial position. Where the 3-substituent was oriented a, steric repulsion with the ethylene bridge caused flattening of the piperidine chair a t the C-3 end (105b). I n order to determine the effect of esterification on the conformational preference of tropine and pseudotropine, PMR studies were made on their acetates and benzilates as well as on atropine. On the basis of half bandwidths of the C-3 hydrogen, it was concluded that the conformation of the piperidine moiety was unaffected by esterification of the alcohol function (269). A tropane analog 222 (191)of meperidine (223) was at one time (270, 271) considered to have a large skew-boat population (as shown) on the basis of analogy with a distorting interaction between the a-phenyl group and the ethylene bridge of the 3b-benzoyl-3a-phenyl analog 224 (272). With the advent of NMR spectroscopy a detailed analysis of these compounds led to the conclusion that the meperidine analog actually exists
d PPh
222
COOEt
COOEt
CH.-N "
223
2 24
2.
TROPANE ALKALOIDS
159
in a chair conformation (225) while the 3-benzoyl compound (224) still appeared to have a boat conformation (273). These conclusions were based to a large extent upon comparison of half bandwidths of various proton signals with those of tropanes of established or very probable configurations. Thus, 3cr-(diphenylhydroxymethyl)tropan-3~-ol (226)
Ph
225 226
showed strong intramolecular hydrogen bonding and was considered to be a model of a boat conformation. The effect of 3a-groups on the 6 values of the endo 6,7-proton resonances was pertinent t o the structural arguments. The correct assignment of the resonances related to these protons was, therefore, quite important. Another NMR study of this same problem (45) came to the same conclusion that the meperidine analog (225) has a chair conformation but that it is considerably flattened (227). Evidence was presented that
CHaN CH,N
Ph
227 228
Ph
the 3-benzoyl intermediate discussed above is in the form of a flattened chair (228) and not a boat. The epimers (229 and 230)of the two compounds in question were available for this study. Carbonyl-nitrogen
CHDN
A$Ph COOEt
229
Jk$l?h OHC\Ph
230
160
ROBERT L. CLARKE
interactions of the kind that would be expected to occur in a boat form such as 224 are known to introduce large up-field shifts in the 13Ccarbonyl signal (274).There is a negligible difference in the 13C-carbonyl signals of epimers 228 ( =224) and 230. The proximity of a carbonyl to the nitrogen of such a boat form (224) should cause a difference in N methyl shift. There is no difference in N-methyl resonance position between ester 227 (flattened chair) and the ketone in question (224 versus 228). It should be noted that there are reversals in the assignments of the proton resonances for the equatorial hydrogens a t C-2(4) and a pair of those at C-6(7)in these two NMR structural studies. I n the latter work, the models for assignment of the C-6(7) protons were two 2,4-tetradeuterated tropanes. N-Oxides were discussed in Section IV, B, but attention is called here to the very clear 220 MHz NMR spectra of the two isomeric oxides of tropine in CD30D. These data were used in assigning configurations to the two N-oxide isomers (71).The mass spectra of these two oxides have been recorded (70). Correlations between NMR shifts and structure have also been investigated for the isomeric N-oxides of hyoscyamine and hyoscine. I n addition, the mass spectral fragmentation patterns of these oxides were given (28). The advantage of chemical ionization (CI) mass spectrometry over conventional electron impact (EI)mass spectrometry was demonstrated with homatropine among other alkaloids (275). I n CI mass spectrometry, the quasimolecular ion M + 1 is invariably more abundant than is the molecular ion in EI spectrometry. I n the case of homatropine (231) the CI method gave a moderately strong M + 1 peak and showed an ion at m/e 258 (M + 1 - H,O). I n the EI spectrum this substance gave
bCO-CH-Ph
231
only a weak molecular ion and no ion a t m/e 258. The same research group has reported the mass spectra of cocaine and scopolamine (276). Application of isobutane chemical ionization mass spectroscopy t o
161
the forensic identification of drugs has been reported in considerable detail. Data on 303 drugs and common diluents have been tabulated. Most of these compounds show an MH+ peak with four or fewer fragmentation ions in abundances greater than 10%. Described are atropine, cocaine, homatropine (molecular weight should be 275), hyoscyamine [shows a 237 peak (20y0) not listed for atropine], scopolamine, and tropine (277).An earlier report by this group reported the spectra of 62 commonly abused drugs (278). Fragmentation patterns produced by eleven tropane derivatives under the conditions of electron impact mass spectrometry were related to the nature of the substituents. Unsaturation in the six-membered ring caused preferential fragmentation of the two-carbon bridge. A saturated six-membered ring containing poor leaving groups (OH and CN) underwent preferential fragmentation of that ring (279). Data on defocused metastable ions were obtained for a series of structurally significant fragment ions in the mass spectrum of tropine. These data, in conjunction with parallel information on 6,7-d2-tropine, provide important insights into the details of fragmentation processes (280). A paramagnetic shift reagent, tris(dipivalomethanato)europium(III), has been used to obtain simplified NMR spectra of tropine, pseudotropine, nortropine, tropinone, and nortropinone. Evidence was presented for a distorted chair conformation in the a- and /3-tropines and tropinones. This work demonstrates the applicability of shift reagents where two centers for coordination are present. The order of coordination was secondary amine > secondary alcohol > tertiary amine 2 ketone (281).Further evidence for this flattening (semiplanar form) in tropanes was gathered using Ni(I1) acetylacetonate and Co(I1)acetylacetonate as shift reagents. Tropine benzoate, homatropine, and tropinone were studied (282). An attempt was made by X-ray diffraction analysis to show the conformation of the N-methyl group in 3a-chlorotropane. The crystal proved to be a monohydrate with the water apparently bonded to the nitrogen, so the primary purpose of the investigation was not realized. It was determined, however, that interaction between the chlorine and the ethylene bridge causes a flattening of the C-2, C-3, C-4 portion of the molecule toward the plane established by C-1, C-2, C-4, and C-5 (283). Another approach to this conformational problem also involved 3a-chlorotropane along with 3a-bromotropane. NMR spectroscopy and dipole moment measurement indicated that perhaps up t o lOyoof the
162
ROBERT L. CLARKE
N-methyl groups occupied an axial position and that a flattening of the piperidine chair occurred as described in the X-ray work immediately above (284).
M.AnalyticalMethods
Microchemical identification of methylatropine, methyl homatropine, hyoscine, and hyoscyamine has been accomplished through formation of salts, including reineckates, chloroplatinates, hexacyanoferrates, and chloromercurates (285). Salts of atropine, homatropine, scopolamine, cocaine, and tropacocaine with arenesulfonic acids are sparingly soluble and have sharp melting points (286). Complexes of alkaloids, including tropanes, with potassium tetraiodomercurate (287), radiolabeled (l3II) potassium tetraiodomercurate (288),and antimonycontaining acids (289) have also been studied. Microcrystalloscopic reactions have been used to identify apoatropine and tropic acid in the presence of atropine (290). A rapid and sensitive gas-liquid chromatographic method (GLC) is described for detecting small amounts of ecgonine and benzoylecgonine in cocaine. It is necessary to silylate these polar substances in order to achieve adequate volatility (291).A similar procedure was used for the detection of cocaine and its principal metabolite, benzoylecgonine (BE), in urine. Separate simultaneous determinations of cocaine and BE were accomplished by analyzing both a methylated (combined cocaine and BE) and an unmethylated (cocaine only) aliquot of the specimen extract. Detection limits were < 0.1 and 0.2 pg/ml for cocaine and BE respectively (291a). A broad study of GLC of tropane alkaloids investigated column materials and packings. Extracts from Datura ferox, D . innoxia, D . stramonium, and Atropa belladonna were used in the study (292).Hyoscyamine and scopolamine (293)and these plus tropine, pseudotropine, nortropine, scopoline, pseudoecgonine, cochlearine, and meteloidine (294) have been separated and identified by GLC. Cocaine has been detected at 20-30 ng/ml by the same technique (295).GLC has also been used for identification of unknown drugs in forensic chemistry (295a). See refs. 277 and 278 for other forensic studies. Simultaneous determination of the major alkaloids of D . innoxia and any fungicide Vitavax present in the sample was also accomplished by this technique (295b).GLC was effective for assay of belladonna but marked differences in results were related to different isolation schemes in sample preparation (295c). Approximately 1000 tons of Duboisia plants are grown yearly to
2.
TROPANE ALKALOIDS
163
obtain the mydriatic alkloid scopolamine. Control analyses by GLC are most satisfactory when phenylacetyltropine is used as an internal standard. Silanization of the samples prevents dehydration to apo forms. The alkaloid content from a commercial bale of Duboisia myoporoides varied with sample position in the bale (235). A GLC-mass spectrometric method for scopolamine sensitive to 50 pg/ml for a 4-ml plasma or urine sample has been reported (296).The method used a deuterated internal standard and involved hydrolysis to scopoline followed by heptafluorobutyrate formation. High-speed, high pressure liquid chromatography has been used (297) for separation of similar tropane alkaloids. It offers the advantages that it is not necessary to liberate free bases prior to analysis as with gas chromatography, the analysis can be performed a t room temperature, and the procedure can be scaled up easily if preparative samples are required. A separate study applied this technique to tropine, scopolamine, and cocaine, among other alkaloids, using six solvent systems and UV monitoring (298).Flow rates and retention times were recorded. A second study by this latter group dealt with atropine, scopolamine and apoatropine ( 2 9 8 ~ ) . Paper and thin-layer chromatography have been used extensively for separation and identification of tropane alkaloids. The following notations are from papers dealing primariIy with these problems. Paper and thin-layer plates (299)and paper alone (300)were used to separate atropine and scopolamine. Gel chromatography has been used for the study of scopolamine in forensic chemical analysis (300a).Iodine is a good reagent for developing spots sinde it is nondestructive (300, 301). Dipping paper chromatographs in 1,-KI produces a blue color for atropine and a red-orange color for hyoscyamine (302).Alkaloid spots have also been located with potassium iodoplatinate and cerium sulfate-H,SO, (303) and with Dragendorffs reagent followed by NaNO, (304). Experiments designed for transferring alkaloids from drug samples directly to chromatoplates a t elevated temperatures using water-charged molecular sieve as a propellant showed that alkaloid decomposition limited the applicability of the process ( 3 0 4 ~ ) . A combination of extractive prOcedures and chromatographic separation allowed the determination of hyoscyamine and scopolamine in Solanaceae within 2% error (305). For the determination of hyoscyamine and scopolamine in the total alkaloids of belladonna, MeOHbenzene was used for plate development, and UV absorption was used for quantitation (306). A similar study was done on atropine and scopolamine (307). For alkaloids in Caucasian scopolia roots and belladonna leaves, 95:5 acetone-lO~oNH,OH was used to separate
164
ROBERT L. CLARKE
hyoscyamine, apoatropine, and scopolamine (308). A 97: 3 acetone NH,OH solvent system separated atropine, apoatropine, Cropine, tropic acid, tropinone, scopolamine, scopoline, scopine, and aposcopolamine (309). I n this case, the colors obtained using fourteen chromogenic reagents were reported. A 6: 3: 1 CH3COC2H5-CH30H-7.5yo NH,OH system effectively separated essentially this same group of bases (310). A partial paper chromatographic separation of hyoscyamine and atropine (dZ-hyoscyamine) is reported that allows estimation of the compositions of mixtures of these substances. A periodate of the alkaloid hydriodide is formed which subsequently liberates iodine (311). No asymmetric reagent was used to impregnate the paper or to develop the system. Five solvent systems were studied in the separation of metabolites of atropine by thin-layer chromatography (290). Partition chromatography on chromatoplates using cellulose coatings allowed the detection of microgram quantities of tropane alkaloids; 0.7 M H,S04 + 0.7 M NaCl was used as the stationary phase and BuOH served as the mobile phase (312).A related study used cellulosecoated plates, a borate/phosphate buffer at pH 6.6, and n-butanol saturated with water. Assay involved a colorimetric method (313). Thin-layer electrophoresis of atropine, homatropine, and cocaine has been accomplished on glass plates coated with cellulose powder using both acidic and alkaline electrolytes (314).Electrophoretic identification of these same substances plus scopolamine and tropacine (3a-tropanyl diphenylacetate) was studied a t a variety of pH values from 1.8 to 8.0 with spot detection by iodine (315).A group of local anesthetics studied by this same technique included cocaine (316).Paper electrophoresis followed by ultraviolet spectrophotometry for assay of atropine, dicaine, cocaine, novacaine and scopolamine was found suitable for forensic purposes (316a). Electrophoretic separation of some Datura and Atropa samples afforded atropine, hyoscyamine, apoatropine, 6-hydroxyhyoscyarnine7 scopolamine, 3,6-ditigloyloxy-7-hydroxytropane, and meteloidine. Their relative migratory rates were recorded a t pH 8 (317).The same method with pH 9.5 borate buffer showed that hyoscyamine is the pharmacologically active principal of the hybrid Atropa martiana (belladonna) (318). Electrophoretic separation has also been used with Duturu bernhardii (319) and D. stramonium (229). The polarographic properties of several amine oxides have been determined including those of 3-tropanol N-oxide (320). Thermal analysis of d and Z-hyoscyamine mixtures containing from 0 t o 50y0 d-hyoscyamine indicated an unbroken series of isomorphic
2.
TROPANE ALKALOIDS
165
mixed crystals. Two polymorphs of 1-hyoscyamine were observed, a stable one melting at 107-109C and a metastable one melting at 104"C, but no polymorphism of atropine was observed (321). Tropic acid ester hydrolase and tropic acid dehydrogenase, enzymes obtained from P s e u d o m o m putidu, were used for enzymatic assay of atropine sulfate, hyoscyamine sulfate, and tropic acid in the 10-7-10-4 M range (322). Atropinesterases from nine Pseudomonas strains were compared with respect to activity and composition (323). Photometry was used t o assay atropine, homatropine, cocaine, scopolamine, and tropazine. Reaction with barbituric acid or thiobarbituric acid in dimethyl or diethyl oxalate was used to develop the chromophore (324).The highest sensitivity was obtained with diethyl oxalate and thiobarbituric acid. Another colorimetric method was used t o determine the alkaloids in Solanaceae extracts (325).The alkaloids were nitrated by a mixture of HNO, and H,SO,, extracted by CH,Cl,, and assayed by the Vitali reaction in dimethyl sulfoxide (326). A third colorimetric method, used on atropine, homatropine, scopolamine, and the methobromides of the last two named, has been based on the hydroxylaminolysis of the ester function t o produce hydroxamic acids followed by addition of ferric ion to produce the colored complex (327). Quantitative methods for determination of microamounts of solanaceous alkaloids are few, none involving direct UV measurement. It has been found that about a 50-fold increase in the UV molar absorptivities of the tropane alkaloids can be achieved via charge-transfer complex formation with iodine in chlorinated hydrocarbon solvents. This allows adequate assay of single drug tablets ( 3 2 7 ~Ultraviolet ). measurement can also be used for determination of scopolamine in the 0.16-1 .OO mg/cm3 range when this alkaloid is complexed as Scopolamine H[Cr(NCS),-(p-toluidine),] (327b). Immunoassay offers the most sensitive measurement available for specific alkaIoidal substances. Benzoylnorecgonine and norcocaine have been derivatized on nitrogen with groups susceptible to diazotization. Coupling of these derivatives to antigenic substances has allowed the preparation of antibodies to cocaine and benzoylecgonine. Other derivatives are also described ( 3 2 7 ~ ) I. n a similar approach, atropine was coupled via its hemisuccinate ester to bovine and serum albumin to produce antibodies (327d). Several variations on and evaluations of pharmacopeia methods of various countries for tropane alkaloid assay have appeared. Four studies related specifically to belladonna (328-331), variations being made in extractive techniques and ultimate titration methods. Drying
166
ROBERT L. CLARKE
the residues from extraction for 2 hours a t 105OC improved the accuracy of the assays for atropine by colorimetry (332).For the determination of total tropane alkaloids in Scopolia roots, extraction was followed by nonaqueous titration of the residue in chloroform solution. Hydrogen chloride in acetic acid served as the acid, crystal violet as the indicator (333).Four British Pharmaceutical Codex mixtures (containing either belladonna or hyoscyamus tincture) were analyzed by the acid-dye technique and the variation from theory noted. Effects of pH and adsorption on the effectiveness of extraction of the alkaloid-dye complex from the mixtures examined were discussed (333a). A critical evaluation of extraction procedures for the determination of atropine and scopolamine in Datura powder showed that variations in results were more likely to be attributable to extractive methods than to determination procedures (334). Eleven different extraction methods have been compared for effectiveness in extracting tropane alkaloids from a variety of plants with special attention given to purification of hyoscyamine and scopolamine (305).Another study was devoted t o separating atropine sulfate in a pure state from other related alkaloids by extractive methods (335). I n a comparison of three extractive procedures on belladonna, hyocyamus, and stramonium leaves, it was found that the same amount of total alkaloids was extracted by 6 days of percolation with ethanol, 30 minutes of elution with gastric juice, and 6 minutes of turboextraction with ethanol (336). I n another procedure, aluminum hydroxide was used to purify the acidic, aqueous ethanolic extract of powdered belladonna leaves. The alkaloids were then separated with a 2.5y0solution of picric acid in chloroform and this organic phase was titrated with sodium dioctylsulfosuccinate ( 3 3 6 ~ ) . Yields of alkaloids in the extraction of Scopolia root with 40yo ethanol were increased by the addition of 0.1yoof Tween 60, Tween 80, or triterpenoid saponins (337). Treatment of powdered D. alba, D. leichhurdtii, and S. carniolica with aqueous ammonia followed by extraction with naphtha No. 1 was an effective first step in the isolation of scopolamine and hyoscyamine from these sources ( 2 0 6 ~ )I.n the process of obtaining scopolamine from I). innoxia, treatment of the acid extracts with proteolytic enzymes removed soluble proteins which formed emulsions during extractive steps (338).
ACKNOWLEDQMENTS
The author greatly appreciates the help of Mrs. Patricia C. Carroll in gathering references, Miss Kristina I. Berglund in typing the manuscript, and Drs. Rudolph K. Kullnig, Frederick C. Nachod, Hiroaki Minatoya, Andrew W. Zalay and Mr. Roman Rakoczy for their help in language translation.
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203. J. F. E. Van Kessel and J. A. C. Van Pinxteren, Pharm. Actu Helv. 45, 164-168 (1970); CA 72, 1 0 3 7 8 2 ~ (1970). 204. Z. Kisgyorgy, G. Racz, and F. Turcsanyi, Famacia (Bucharest) 19,431-436 (1971); CA 76, 23166s (1972). 205. J. Tucakov, G1a-s. Srp. Akad. Nauka U m t . , Od. Med. Nauka 23,55-59 (1971); C A 75, 101221b (1971). 205a. G. Seifert, Herba Hung. 14, 23-28 (1975); C A 83, 175454s (1975). 205b. V. V. Koval'skii, I. F. Gribovskaya, N. I. Grinkevich, M. Ya. Lovkova, and Z. V. Boichenko, U.S.S.R. Pat. 499,857 (1976); C A 84, 163570j (1976). 206. W. C. Evans, A. Ghani, and V. A. Woolley, J. C h m . Soc., Perkin Trans. 1 20172019 (1972). 206a. K. Kagei, K. Okazaki, H. Yamauchi, and T. Chiba, Japan. Kokai 75, 49,412, May 2, 1975; C A 83, 65453h (1975). 207. M. S. Karawya and S. I. Balbaa, Bull. Fac. Pharm., Cairo Univ. 6, 9-13 (1967); C A 73, 77448s (1970). 208. K. Szepczynska, Diss. Pharm. Phr.mac01. 22,3540,333-335 (1970); C A 73,939v, and 74, 1 0 2 9 8 6 ~ (1970). 209. W. C. Evans, A. Ghani, and V. A. Woolley, Phytoehemistry 11, 2527-2529 (1972). 209a. L. Z. Padula, A. L. Bandoni, R. V. D. Rondina, and J. D. Coussio, Planta. Med. 29, 357-360 (1976). 210. W. C. Evans and A.-0. Somanabandhu, Phytochemistry 13, 304-305 (1974). . Balbaa, G. A. El Hossary, and M. S. Karawya, Lloydia 33, 211. A. H. Saber, S. I 401-402 (1970); C A 74, 505360 (1971). 212. A. Khaleque, A. K. M. M. Rahman, Kh. M. Ismail, M. S. Amin, and M. Kiamuddin, Bangladesh J. Sci. Ind. Rea. 9, 79-81 (1974); CA 82, 28529w (1975). 212a. N. Nastev and I. Yankulov, Dokl. S-kh. Akad., Sofia 8, 11-14 (1975); C A 84, 55194f (1976). 213. Z. A. Kerbabaeva and N. N. Shamaeva, Vopr. Bwl. Zhivotn. Raat. Turkm. 1, (1975). 64-68 (1973); C A 83, 1 2 6 8 8 3 ~ 214. R. Zielinska-Sowicka and K. Szepczynska, Diss. Pharm. Phurmzcol. 24, 307-311 (1972); C A 77, 85746k (1972). 215. W. Czabajska, B. Jernas, J. Lutomski, and M. Turowska, Herba Pol. 19, 223-231 (1973); C A 80, 130509k (1974). 216. F. J. Muhtadi, M. M. A. Hassan, and 0. A. Aziz, Bull. Fac. Sci., Riyadh Univ. 5, 1-15 (1973); C A 81, 101848%(1974). 217. P. Singh, Expepientda 26, 211 (1970); Herba Hung. 10,15-20 (1971); C A 77,70805e (1972). 218. V. S. Prabhakar, Y. K. Sarin, and C. K. Atal, Indian J. Pharm. 33, 35-36 (1971). 218a. R. P. Nandi and S. K. Chatterjee, Indian J. Exp. B b l . 13,215-216 (1975); C A 84, 55756v (1975). 218b. G. Verzar-Petri, M. Vincze-Vermes, L. Horvath, I. Baht-Ambro, and T. Szarvas, Acta Pharm. Hung. 45, 167-174 (1975); CA 83, 1 4 2 8 6 5 ~ (1975). 218c. J. Jankulov and K. Alipur, Dokl. S-kh. Akad.. Sofa 8, 47-50 (1975); CA 84, 132796h (1976). 218d. H. D. Shell, M. Carsteanu, A. Nasta, I. Cornoiu, 0. Gozia, and T. Bentia, Stud. Cercet. Biochirn. 19, 101-107 (1976);CA 85, 1 0 7 8 9 1 ~ (1976). 218e. R. P. Nandi and S. K. Chatterjee, Indian Biol. 7, 31-35 (1976); CA 85, 74989f (1976). 218f. A. I. Gabr, E. N. Abou-Zied, M. R. Shedeed, and S. E. E l Sherbeeny, Herba Pol. 21, 192-200 (1975); C A 84, 2674711 (1976).
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2.
TROPANE ALKALOIDS
177
247. M. Tabata, H. Yamamoto, N. Hiraoka, A. Oka, K. Kawashima, and M. Konoshha, Shoyakugaku Zasshi 23, 83-88 (1969); CA 73, 73844v (1970). 247s. Y. Watanabe, I. Yasuda, T. Seto, K. Nakajima, and Y. Nishikawa, Tokyo ToritsU Ebei Kenkyuaho Kenkyu Nempo 26, 90-92 (1975); CA 85, 10345k (1976). 248. M. Tabata, H. Yamamoto, N. Hiraoka, and M. Konoshima, Phytochemistry 11, 949-955 (1972). 249. M. Szymanska, Pol. J . Pharmacol. Pharm. 25, 201-206 (1973); CA 79, 102854e (1973). 250. S. A. Minina and E. A. Marchenko, Rmtit. Reaur. 9, 203-205 (1973); CA 79, 15907f (1973). 251. S. A. Minina, L. P. Mashkova, andL. A. Kulikova, Rmtit. Reaur. 5 , 385-390 (1969); C A 72, 3978% (1970). 252. M. Gorunovic, N. Prum, and J. Raynaud, Plant. Med. Phytother. 4, 286-291 (1970); C A 74, 108125rn (1971). 253. M. Yankulova and I. Yankulova, Dokl. Akad. Nauk Bolg. 4, 299-307 (1971); C A 77, 45657a (1972). 254. M. Gorunovic and P. Lukic, Acta P h r m . Jugosl. 22, 69-71 (1972); C A 77, 79580k (1972). 255. G. M. Ulicheva, Rmtit Resur. 6, 528-534 (1970); C A 74, 95405a (1971). 256. I. Barene and S. A. Minina, Rastit. Resur. 7 , 124-128 (1971);CA 74,108131k (1971). 257. B. A. Samoryadov and S. A. Minina, Khim. Prir. Soedin. No. 7, 209 (1971); CA 75, 31332n (1971). 258. I. Barene and S. A. Minina, Khim. Prir. Soedin. No. 7 , 379-380 (1971); CA 75, 115920r (1971). 259. G. M. Ulicheva, Rastit. Resur. 7 , 18-24 (1971); CA 74, 108126n (1971). 260. S. A. Minina and I. Barene, Bwl. Akt. Veshcheatva F l q Fauny Dal'n. Vost. Tikhogo Okeana 22-23 (1971); C A 77, 111461k (1972). 261. N. I. Ryabova, Rastit. R w r . 9, 548-550 (1973); CA 80, 1 0 5 8 5 6 ~ (1974). 261a. S. A. Minina, T. V. Astakhova, and N. V. Nazarova, Rastit. Resur. 11, 493-496 (1975); C A 84, 56481j (1976). 262. W. C. Evans, A. Ghani, and V. A. Woolley, Phytochemistry 11, 470-472 (1972). 263. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochran, and F. M. Shell, Ace. Chem. Res. 7 , 46-51 (1974). 264. L. Simeral and G. E. Maciel, Org. Magn. Reson. 6, 226-232 (1974). 265. P. Pauling and T. J. Petcher, Chem. Commun. 1001-1002 (1969). 266. V. S. Dimitrov, S. L. Spasov, and T. Radeva, J. Mol. Struct. 27, 167-176 (1975). 267. P. Scheiber and K. NBdor, Arzneim.-Forsch. 25, 375-378 (1975). 268. K. NBdor and P. Scheiber, Arzneirn.-Forsch. 22, 459-462 (1972). 268a. H.-J. Schneider and L. Sturm, Angew. Chem. Int. Ed. Eng. 15, 545-546 (1976). 269. A. F. Casy and W. K. Jeffery, Can. J . Chem. 50, 803-809 (1972). 270. A. F. Casy, Prog. Med. Chem. 7 , 265-276 (1971). 271. P. S. Portoghese, A. A. Mikhail, and H. J. Kupferberg, J . Med. Chem. 11, 219-225 (1968). 272. M. R. Bell and S. Archer, J . Am. Chem. SOC. 82, 151-155 (1960). 273. A. F. Casy and J. E. Coates, Org. Magn. Reson. 6, 441-444 (1974). 274. T. T. Nakashima and G. E. Maciel, Org. M q n . Reson. 4, 321-326 (1972). 92, 1590-1597 275. H. M. Fales, H. A. Lloyd, and G. W. A. Milne, J . Am. Chem. SOC. (1970). 276. H. M. Fales, G. W. A. Milne, and N. C. Law, Arch. Mass Spectral Data 2, 654-657 (1971).
178
ROBERT L. CLARKE
277. R. Saferstein, J.-M. Chao, and J. Manura, J . Forensic Sci. 19, 463-485 (1974). 278. R. Saferstein and J.-M. Chao, J. Assoc. Off. Anal. Chem. 56, 1234-1238 (1973). 279. J. E. Dewhurst, J. J. Kaminski, and J. H. Supple, J. Heterocycl. Chem. 9, 507-511 (1972). 280. D. H. Smith, A. M. D d e l d , and C . Djerassi, Org. MmsSpectrom. 7,367-381 (1973). 281. G. S. Chappell, B. F. Grabowski, R. A. Sandmann, and D. M. Yourtee, J . Pharm. Sci. 62, 414-419 (1973). 282. M. Ohashi, I. Morishima, K. Okada, T. Yonezawa, and T. Nishida, J. Chem. Soc. D 34-35 (1971). 283. M. Vooren, H. Schenk, and C. H. MacGillavry, Acta Crystallogr. (Sect. B) 26, 1483-1487 (1970). 284. P. Scheiber, G. Kraiss, and K. NQdor, J. Chem. SOC. B 1366-1369 (1970). 285. 0. N. Yalcindag and E. Onur, Turk. Hi$. Tecr. BiyuZ. Berg. 29, 130-142 (1969); CA 72, 1 3 6 4 5 7 ~ (1970). 286. Z. Zakrzewski and J. Jarzevinski, Farm. Pol. 29, 627-631 (1973); C A 80, 124796% (1974). 287. G. Szasz and L. Buda, Fresenius' 2. AnaZ. Chem. 253, 361-363 (1971); CA 74, 94154f (1971). 288. A. M. Nour, A. A. Saleh, A. E. M. Habib, N. Hamad, and A. F. Shalaby, lsotopenpraxis 8, 274-275 (1972); C A 78, 23812r (1973). 289. T. P. Churina, Fiz.-Khim. Probl. Sovrem. Bwl. Med., Mater. Konf., 1970 216-222 (1970); CA 80, 7004q (1974). 29, 290. 0. A. Akopyan, L. V. Vrochinskaya. and L. V. Romanchenko, Farm. Zh. (Kiev) 57-60 (1974); C A 82, 51258r (1975). 291. J. M. Moore, J. Chromatogr. 101, 215-218 (1974). 291a. J. E. Wallace, H. E. Hamilton, D. E. King, D. J . Bason, H. A. Schwertner, and S. C. Harris, Anal. Chem. 48, 34-38 (1976). 292. R. Achari and F. Newcombe, Planta Med. 19, 241-248 (1971). 293. T. Minamikawa, J . P h r m . Soc. Jpn. 90, 1457-1460 (1970); B-L. W. Chu and E. S. Mika, J. Pharm. Sci. 59, 1508-1510 (1970). 294. H. W. Liebisch, H. Bernasch, and H. R. Schutte, 2. Chem. 13, 169-170 (1973). 295. J. W. Blake, R. S. Ray, J. S. Noonan, and P. W. Murdick, Anal. Chem. 46,288-289 (1974). (1975). 295a. B. Kaempe, Arch. Pharm. Chem. 81, 1183-1190 (1974); C A 82, 1 3 3 6 2 5 ~ 295b. G. Verzar-Petri and M. Y. Haggag, Herba Hung. 15, 85-96 (1976); C A 85, 1970h (1976). 2950. D. K. Wyatt, W. G. Richardson, B. McEwan, J. M. Woodside, and L. T. Grady, J. Pharm. Sci. 65, 680-684 (1976). 296. W. F. Bayne, F. T. Tao, and N. Crisologo, J . Pharm. Sci. 64, 288-291 (1975). 297. M. H. Stutz and S. Sass, Anal. Chem. 45, 2134-2136 (1973). 298. R. Verpoorte and A. B. Svendsen, J. Chromatogr. 100, 227-230, 231-232 (1974). 298a. R. Verpoorte and A. B. Svendsen, J. Chromatogr. 120, 203-205 (1976). ( .Petrovic, and M. Gorunovic, Arh. Farm. 19, 235-244 (1970); C A 73, 299. B. Pekic, I 18499m (1970). 300. A. Puech and M. Jacob, Ann. Pharm. Fr. 29, 437-441 (1971); C A 75, 101327r (1971). 300a. 0. A. Akopyan and S. M. Shevchuk, Farmatriya. Resp. Mezhved. Sb. 71-74 (1975); CA 85, 1480511 (1976). 301. J. H. Copenhaver, D. R. Cronk, andM. J. Carver, Microchem.J. 16,472-479 (1971). 302. A. Puech and J. L. Reffay, Ann. P h a m . Fr. 27, 483-488 (1969); C A 73, 7130h (1970).
2.
TROPANE ALKALOIDS
179
303. A. Verweij, R. DeJong-de Vos, and H. G. J. Teisman, J. ChrMnatogr. 69, 407-410 (1972). 304. A. Puech, M. Jacob, and D. Gaudy, J. Chromtogr. 68, 161-165 (1972). 304e. E. Stahl and W. Schmitt, Arch. Pharm. (Weinheim, Qer.) 308,570-578 (1975); C A 83, 197866e (1975). 30.5. B. Pekic, K. Petrovic, and M. Gorunovic, Arh. Farm. 21, 209-213 (1971); C A 76, 96502h (1972). 306. C. D. Padha, M. C. Nigam, and P. R. Rao, J. Inat. Chem., Calcutta 43 (Pt. l), 5-9 (1971); C A 75, 59560j (1971). 307. T. BiOan-FGter, J . Chromtogr. 55, 417-421 (1971). 308. T. A. Pletneva, I. S. Simon, and Y. V. Shostenko, Khim.-Farm. Zh. 7,53-56 (1973); C A 80, 30740k (1974). 309. J. Polesuk and T. S. Ma, Mikrochim. Acta. 67Ck676 (1970). 310. E. Weigert, Rev. Fac. Farm. B w q u h . Univ. Fed. St. Maria 15, 61-67 (1969); C A 74, 3187311 (1971). 311. A. Puech and M. Jacob, Ann. Phurm. Fr. 29, 437-441 (1971); C A 75, 101327r (1971); J. Pharm. Belg. 26, 207-210 (1971); CA 75, 528542 (1971); see also Puech and Reffay (302). 312. I. Yankulov, Rastenievwl. Nauki 11, 59-68 (1974); C A 81, 11670513 (1974). 313. J. Grujic-Vasic, S. Ramic, and R. Popovic, Ulaa. Hem. Tehnol. Bosne Hercegovine 18, 41-46 (1970); C A 79, 70260q (1973). 314. A. S . C. Wan, J. Chromatogr. 60, 371-376 (1971). 315. L. V. Pesakhovich and M. I. Radyuk, Farmatsiyu (Moscow) 19, 58-60 (1970); CA 73, 1 3 4 0 0 7 ~ (1970). 316. L. V. Pesakhovirh and M. I. Radyuk, Fk-Khirn. Probl. Sovrem. Biol. Med., Mater. K ~ n f .1970 , 171-174 (1970); C A 80, 7 0 0 3 ~ (1974). 316a. V. V. Mikhno, I. G. Postrigan, P. P. Lutsko, and G. K. Levitskaya, Farm. Zh. (Kiev) 31, 59-62 (1976). 317. S. Kisgyorgy, Rev. Med. (Tirgu-Mures, Rom.) 17, 87-89 (1971); C A 75, 115884g (1971). . ! ' r a w . SOC. P h a m . Montpellier 30, 55-60 (1970); C A 73, 318. R. San Martin Casamada, ! 69770a (1970). 319. K. Szepczynska, D k s . Pharm. Phamnacol. 22, 35-40 (1970); CA 73, 939v (1970). 320. H. Hoffmann, Arch. Pharm. (Weinheim, Uer.) 304, 614-623 (1971); C A 75, 147596f (1971). 321. M. Kuhnert-Brandstaetter and R. Linder, Mikrochim. Acta 1, 513-520 (1976); C A 84, 184960b (1976). 322. H. 0. Michel, E. Hackley, and D. N. Kramer, Anal. Biochem. 36, 294-302 (1970). 323. R. A. Oosterbaan and F. Berends, Proc. K. Ned. Akad. Wet., Ser. C 74, 158-166 (1971); C A 75, 30322x (1971). 324. G. I. Kudymov, A. A. Kiseleva, and M. V. Mokrouz, Tr. P e r m k . Farm. Inst. NO. 3, 111-113 (1969); C A 75, 4 0 4 9 7 ~ (1971). 325. J. Lemli, Phurm. Weekbl. 106, 207-213 (1971); CA 74, 146433t (1971). 326. G. Schwenker, Arch. P h a m . (Weinheim, Uer.) 298, 826838 (1965). 327. J. A. Feldman and B. J. Robb, J. Pharm. Sci. 59, 16461647 (1970). 327a. C. Gomaa and A. Taha, J. Pharm. Sci. 64, 1398-1400 (1975). 327b. D. Oprescu, S. Imreh, M. Brailoi, and D. Bucur, Rev. Chdm. (Bucharest) 27, 71-72 (1976); C A 84, 184961~ (1976). 3270. R. K. Leute and G. Bolz, U.S. Pat. 3,888,866 (1975). 327d. A. Fasth, J. Sollenberg, and B. Sorbo, Acta Pharm. Suec. 12, 311-322 (1976); C A 84, 29013b (1976).
180
ROBERT L. CLARKE
328. M. Dorer and M. Lubej, Arch. Pharm. Ber. B@ch. harm. Urn. 305,273-276 (1972); C A 77, 39316x (1972). 329. A. Puech, M. Jacob, J. Dupy, and J. Grevoul, J . Pharm. BeZg. 24, 389-396 (1969); CA 72, 82995b (1970). 330. A. Puech, M. Jacob, J. Dupy, and J. Grevoul, J . Pharm. BeZg. 26, 520-524 (1971); CA 77, 393268. (1972). 331. W. Wisniewski and H. Piasecka, Acta: Pol. Pharm. 28,55-58 (1971);C A 75,25456q (1971). 332. W. Wisniewski and S. Gwiazdzinska, Acta Pol. Pharm. 29, 347-348 (1972);CA 77, 137031~ (1972). 333. I. S. Simon, T. A. Pletneva, T. N. Gubina, and Y. V. Shostenko, Khim.-Farm. Zh. 4, 58-60 (1970);C A 74, 34639h (1971). 333a. S . A. H. Walil and S. El-Masry, J . Pharm. Sci. 65, 614-615 (1976). 334. M. J. Solomon and F. A. Crane, J. Pharm. Sci. 59, 1680-1682 (1970). 335. Y. V. Shostenko, I. S. Simon, and T. N. Gubina. Otkqtinya, Izobret., Prom. Obraztsy, Tovarnye Z m k i 51, 68 (1974);C A 80, 146395f (1974). 336. S . Bukowski and A. Bartosiak, Farm. Pol. 28,125-127 (1972);C A 77,9559m (1972). 336a. A. L. H. DeDujovne and J. Helman, Rev. Farm. (BW?%08 Aires) 117,66-72 (1975); CA 85, 2154g (1976). (1972). 337. L. P. Khudyakova, Aktual. V o w . Farm. 1, 127-129 (1970); C A 76,63129~ 338. V. Kamedulski, B. Bozhanov, I. Tonev, and M. Dzherova, Barmatsiya (So$a) 25, 11-15 (1975);C A 85, 831526 (1976).
-CHAPTER
3 -
NUPHAR ALKALOIDS*
JERZY T. W R ~ B E L
University of Warsaw Warsaw, P o l a d
I. Introduction ........................................................ 11. C,, Alkaloids ....................................................... A. Chemistry ....................................................... B. Absolute Configuration............................................ C. New Compounds ................................................. 111. Sulphur-ContainingC,, Alkaloids ..................................... A. C,, Alkaloids of Sulfoxide Structure ................................ B. C,, Alkaloids of Carbinolamine Structure.. .......................... IV. Mass Speotrometr y .................................................. V. Total Synthesis of CI5 Nuphar Alkaloids ............................... VI. Biosynthesis ........................................................ References .........................................................
181 181 181 185 186 195 197 198 204 211 213 213
I. Introduction
Nuphar alkaloids were extensively studied in the last decade mainly in Poland and Canada, as well as in Japan, the United States, and the Soviet Union. Several new C15 and thio-C,, alkaloids were isolated. Special attention was paid to conformational and configurational problems studied by various chemical and spectral methods. The fragmentation of both C,, and thio-C,, systems was studied by mass spectrometry, and general conclusions were formulated concerning the mechanism of fragmentation and its structural implications. Preliminary biosynthetic studies were carried out using I4C-labeledmevalonic acid.
I I . C,, Alkaloids
A. CHEMISTRY Nupharidine and deoxynupharidine were the most extensively studied C,, alkaloids. Arata et al. ( 1 ) oxidized nupharidine (1) into dehydrodeoxynupharidine (2) using ferric nitrate. The reaction was
* For the first review on Nuphar alkaloids by J. T. Wrbbel, see Vol. IX of The Alkaloids. Chapter 10, p. 441.
182
shown to have a more general preparative value, as exemplified by oxidation of 4-phenyl-quinolizidine N-oxide. Several derivatives of deoxynupharidine (3), substituted in the furan ring, were prepared
b///,,/M h
Me
3a 3b
3e
R = NO1 R = COCH, R
=
-c>
NO2
using certain electrophilic reagents (2). 5-Acetyl-deoxynupharidine was transformed to the 3-hydroxy-2-methylpyidylderivative (4) on heating with aqueous ammonia and ammonium chloride (2).
Me
I
Me
4
Polonovski transformation of ( + )-nupharidine carried out in a large excess of acetic anhydride resulted in A6-enamine( 5 ) (3).Hydrogenation of 5 resulted in ( - )deoxynupharidine and ( - )-7-epideoxynupharidine
3.
N U P H A R ALKALOIDS
183
Me
in a 7:1 ratio. Enamine 5 was transformed in two steps to (-)nupharamine (7) with 59y0overall yield ( 3 )(Eq. 1). Oxidation of 5 with osmium tetroxide-paraperiodic acid in pyridine-water-dioxane solution yield. Thelatter compound, results in the formamidoketone (6)with 95y0 when refluxed in ether with large excess of methylmagnesium iodide yielded 7.
5----5-
080
(1)
a,lr
( - ) Nupharamine
6
A mechanistic interpretation of the Polonovski transformation ( 3 ) was attempted. The A6-enamine ( 5 ) was converted to deoxynupharidine-6p,7/3-d2(8)by catalytic addition of deuterium. The stereochemistry of the deut'erium atoms in 8 was based on the preferred cis catalytic hydrogenation of the a side of 5 and on NMR spectra. The C-6,equatorial hydrogen quartet (T = 7.30) of 3 appears as a singlet in 8, and the C-6g axial hydrogen quartet (T = 8.12) of 3 is absent in 8. From 8, a derivative corresponding t o 1 was prepared. The latter, treated under the Polonovski conditions, resulted in the corresponding A6-enamine (9) (Eq. 2 ) . The mass and NMR spectrometric studies
Me Me
184
demonstrated that the hydrogen atom eliminated in the Polonovski transformation was the 6a-hydrogen. The oxidation of deoxynupharidine to nupharidine was found t o be almost three times faster than the oxidation of 7-epideoxynupharidine. This was explained in terms of oxidation of deoxynupharidine with inversion on nitrogen to give a cis-fused quinolizidine N-oxide (10) (Eq. 3). The cis-fused conformation of nupharidine was confirmed by
H I
X-ray studies. I n view of the cis ring fusion in 1, the Polonovski transformation was considered to be a trans8 elimination; the mechanism would then involve the steps shown in Eq. 4.
Me
Me
Me
Me
( + )-Nupharidine was transformed to A3-dehydrodeoxynupharidine (11) using a modified Meisenheimer rearrangement ( 4 ) (Eq. 5 ) .
Me
(5)
l -
11
3.
185
The mechanism was shown to involve the steps shown in Eq. 6.
Me
F
OH
11
(6)
B. ABSOLUTE CONFIGURATION
The absolute configuration of ( - )-deoxynupharidine and other C,, alkaloids (5) was questioned first by Turner et al. (6), who ascribed the R-configuration to the ( - )-a-methyladipic acid; the previously proposed absolute configuration of ( - )-deoxynupharidine 12 was predominantly based on the assumption that the ( - )-a-methyladipic acid obtained by oxidation of 3 has the S-configuration. Further work
Me
12
13
by LaLonde et al. (7) on the synthesis of (-)-(R)-a-methyladipic acid supported this suggestion. The final proof was supplied by Oda and Koyama (8) in the form of an X-ray analysis. The above results indicate that the absolute configuration of (-)deoxynupharidine is represented by formula 13. This reassessment required a correction of the absolute configuration of other C,, alkaloids, e.g., dehydrodeoxynupharidine (14), nupharamine (15), anhydronupharamine (16), nuphamine (17), and 3-epinuphamine (18). The corrected absolute configurations for the above alkaloids are given by structures 14-18.
186
h..
14
Me
Me
Me
15
16
18
C. NEW COMPOUNDS
1. 7-Epideoxynupharidine (19)
This alkaloid was isolated by LaLonde et al. (9, 10) from Nuphar luteum Sibth. et Sm. subsp. variegatum. The structure was confirmed by IR and NMR spectra and hydrogenation of As-dehydrodeoxynupharidine ( 5 ) ,which produced deoxynupharidine (3) and the 7-epiisomer
(19).
Me
19
The NMR spectrum of 1 9 displayed methyl resonance doublets a t T (J = 3 and 5.4 Hz, respectively). I n comparison with NMR data for deoxynupharidine (3),the axial methyl groups with lower field signals and larger splittings and the equatorial methyl groups with higher field signals and smaller splittings can be correlated-a
9.08 and 9.26
3.
187
phenomenon well-known in quinolizidine chemistry (IOU).The absolute 9 configuration of 7-epideoxynupharidine represented by structure 1 follows correlation through 5 with deoxynupharidine (3).
2. Nuphenine (20) and Anhydronupharamine (24)
20
Nuphenine (20) was isolated first by Forrest et al. (11, l l a ) . Its molecular formula was determined as C,,H,,NO (mw = 233). The I R spectrum shows N-H (3310 cm-l), Bohlmann bands (2800 and 2730 cm-l), furan (1505, 880 cm-l); the NMR spectrum indicates the presence of a substituted double bond (multiplet at 4.88 7)Nuphenine can be hydrogenated either to a dihydro compound (21)or to hexahydro derivative (22) (Eq. 7 ) . The 4.88 signal is absent in the
20
22
21
NMR spectrum of 21, and the peak a t 8.3 r (6H,S) in nuphenine is shifted to 8.75 T (6H,d);this, together with the peaks at mle 164 (M-69) in the mass spectrum of 20 and at mle 168 in the spectrum of 22, confirms the presence of the (CH3)2C=CH-CHz(m/e 69) group in 20. Easy loss of this group suggests that it is located in the position alpha to nitrogen in the piperidine ring. Since H, is split by only one ring proton, the methyl group is assumed to be located on the adjacent carbon; the protons H, and H, with a coupling constant of 2.5 Hz must be in an axial-equatorial or equatorial-equatorial relation to one another (12). The presence of bands a t 2800 and 2730 cm-l in the I R spectrum of nuphenine was taken as evidence for t.wo hydrogens axial to the nitrogen atom. The proposed configuration ofnuphenine is shown in 23.
188
~ b - k - ~ e \ /Me
He /C=C\Me 23
Isomeric with nuphenine is anhydronupharamine (24) isolated by Arata et al. (13, 14) from Nuphar japonicum DC. It proved t o be identical with the dehydratation product of ( - )-nupharamine (15) and therefore its configuration should be as in 24.
24
3. Nuphamine (17)
17
The chemistry of this alkaloid was further studied and its configuration was related to deoxynupharidine (3) and nupharamine (15). The transformations in Eq. 8 have been effected. On the basis of Eq. 8, nuphamine is thought to have configuration 17. A study of the configuration around the double bond in nuphamine led to the conclusion that in the side chain the methyl group and hydrogen were in the trans position (15).This deduction is based on a general observation that in the X-CH,-C(CH,)=CH,-Y system a trans relationship between the methyl group and the vinyl proton results in a higher r value
3.
17
189
Na2C03, C H d
24
( A T = 0.06-0.07) for the methyl protons than that observed for the cis isomer. Thus, the absolute configuration 27 of nuphamine (17) was established:
4. 3-Epinuphamine (28)
(C,,H2,N02)
The alkaloid was isolated by LaLonde et al. (16) from Nuphar luteum subsp. variegatum and was shown to have configuration 28. Its molecular formula was confirmed by mass spectroscopy. The IR and NMR spectra indicate the presence of a %fury1 group. Attachment of
190
this group to the carbon a to nitrogen (C-6) was concluded from the presence of the proton (3.58 6) deshielded by the fury1 group and the nitrogen. The presence of OH and NH groups was established in the conversion of 28 to an N,O-dibenzoyl derivative. The presence of a
28
trisubstituted double bond was indicated by the I R and NMR spectra; the latter showed a hydroxymethyl group (3.93 6, 2H, broad singlet), a vinyl methyl group (1.65 6, 3H, broad singlet), and a methylene group. The trans stereochemistry of the double bond was based on the character of the vinyl proton signal in the NMR, as it was shown in nuphamine (15).Oxidation of 28 with MnOz resulted in an aldehyde (29), giving additional support to the proposed double bond stereochemistry. The
FYMe Me
29
UV spectrum of this aldehyde was in accord with known trans-2-methyl2-pentanal. a-Attachment of the side chain to nitrogen was consistent
with the appearance of an ion at m/e 164 ( l O O ~ o )in the mass spectrum. The NMR spectrum showed the C-2 proton as a triplet of doublets, which could be explained as a coupling to the side chain methylene group and to a single proton. This implied substitution a t C-3 of a methyl group whose presence is indicated by a doublet a t 0.99 6. The substitution pattern in piperidine was determined by converting both the N,O-dibenzoyl derivative (30) and nuphenine benzamide to the aldehyde (32):
0
30 R = CH,OCOCeH,, R = CeH5C0 31 R = Me, R = CeH,CO 32
3.
191
The presence of an axial methyl group at C-3 is implied by a doublet a t 0.99 6, which is a t a lower field than the resonance (0.91 6) displayed by the equatorial methyl of nuphamine. Other characteristics of NMR spectra are consistent with this assignment.
5 . Nupharolidine (33) (C,,H2,N02)
33
This alkaloid isolated from the rhizome of Nuphar luteum by Wr6bel and Iwanow ( I Y ) , was the first among the C,, alkaloids to be shown to have its hydroxyl group situated in the quinolizidine ring. The suggested structure of this alkaloid was based on spectroscopic correlation (IR, NMR, and mass spectra) with three other C,, basesdeoxynupharidine (3),castoramine (34), and nuphamine (17). The
Me
34
R 1= CHaOH, Ra = H
crucial observations pertaining to the structure beside the transquinolizidine and a B-substituted furan ring indicated the presence of two
(7
= 6.35, and 4.75,; IR, 3342 cm-l). The presence of two methyl groups, which appear as two doublets, ruled out the presence of a hydroxymethyl group and eliminated the possibility of C-1 and C-7 being the points of OH substitution. Since a strong signal a t mle 178 (fragment 35) was observed in the mass spectrum the presence of an OH group at C-6 position was also ruled out.
\ CH-CH, /
groups
(T
9.12 and 8.80; doublets),
\CH,-O& /
192
Me
35
The presence of the fragment 35 and of two others at mle 71 and 206 to which structure 36 and 37 were ascribed, respectively, point to C-9 as the location of the hydroxyl group. Thus, nupharolidine is thought to have structure 33.
36
m/e 71
37
m/e 206
6. Nupharolutine (38) (C,,H,,NO,)
Nupharolutine is another C,, alkaloid with a hydroxyl group. It was isolated and its structure was established by the Polish-Canadian group of workers (18).It is isomeric with nupharidine (1) and castoramine. Structure 38 for nupharolutine was based on spectroscopic and chemical data.
Me
38
3.
NUPHAR ALKALOIDS
193
The IR spectrum shows the presence of an intermolecularly bonded hydroxyl group and a trans-quinolizidine system. Unsuccessful attempts at acetylation indicate the tertiary character of the hydroxyl. The NMR spectrum of the new alkaloid shows a doublet centered a t 0.92 and a singlet (3H) at 1.21 6. The singlet peak and its chemical shift are compatible with a -C!--C(CH3)OH-C--
Other signals in the NMR spectrum were in accord with those observed for deoxynupharidine and indicated the presence of a p-substituted furan ring in the equatorial position (C-4-Haxial quartet 3.03 8 , J = 8.3 and 6.0 Hz). The final data for structure 38 were obtained from the mass spectrum. High resolution studies gave the composition of the ions observed, thereby giving further insight into the fragmentation process. The fragmentation is discussed later with that of other Nuphar alkaloids. Nupharolutine was correlated wiih deoxynupharidine (3) as in Eq. 9.
I I I I
I I
grouping in the molecule.
This sequence offers the final proof for the proposed structure and for the absolute configuration of nupharolutine. A dimeric compound related to nupharolutine was isolated by LaLonde et al. (19).Spectroscopic data indicate structure 39. This structure was confirmed by a synthesis beginning with dehydrodeoxynupharidine (14) (Eq. 10). Osmium tetroxide oxidation of 14 yielded diol 40, which wa,s transformed upon dehydration into 39, borohydride reduction of which generated a mixture of 41 and 42.
Me
Me
39
194
14
40
I 39
b R
NaBH
Ri
Qr
41 42
Rl = O H , R, 5 H Rl = H R Z = OH
7. Epinupharamine (Epi-15) (C,,H,,NO,)
3-Epinupharamine (epi-15) was isolated by Forrest and Ray who established its structure. Its structure was proved on the basis of its spectra and by its synthesis from nuphenine (20). Mass spectrometry confirmed the molecular formula and the presence of the 3-methyl-3hydroxybutyl side chain (peak a t mle 164). The IR and NMR spectra
Epi - 15
showed the presence of the hydroxyl group (3575, 3150 em-, and T = 7.35) and the furan ring (IR, 1500, 1170, and 875 cm-l; NMR, 2.63 (2H), 3.57 (1H) T ; CH-CH, (ring) 9.03~d and a gem-CH, 8.83 T, 8.75 T). This assignment of the structure and stereochemistry was verified by the conversion of nuphenine (20) into a compound identical with the naturally occurring epi-15.
3.
195
1 1 1 . Sulfur-ContainingC,, Alkaloids
Thiobinupharidine (43) (C3,H,,N,02S)
"As
43
It was shown earlier (20, 21) that 43 is isomeric with neothiobinupharidine (44) and both 43 and 44 have almost the same characteristic structural pattern (quinolizidine, furan, -S-CH,-, two methyl groups, and similar pK, values). Extensive spectroscopic studies led to deduction of the structure and of the relative configuration of 43. The structure has been firmly established and the absolute configuration has been determined by a study of the crystal structure of thiobinupharidine dihydrobromide dihydrate (22). The structure of thiobinupharidine was established by Wr6bel and MacLean (22)by comparing the IR, NMR, and mass spectra with those previously obtained for neothiobinupharidine (44) (20, 21). The I R and NMR studies (23)of the alkaloid in question, of some model compounds, and of reduction products of biscarbinolamines led LaLonde to the same conclusion. Equimolecular solutions of 43 and 44 examined under the same conditions showed Bohlmann bands of nearly equal intensities. This indicates the presence of two trans-quinolizidine rings in 43. High-resolution mass measurements showed identical compositions of the major ions in the spectra of 43 and 44. The NMR spectra of the two alkaloids have been examined a t 220 MHz, and the anomalies of the earlier studies (20, 21) have been clarified. There is a signal of area 6 centered a t 6 0.91 ( J = 5 Hz) assignable to two C H m , groups (compare 6 0.85, J = 5.5 Hz for 44 and 6 0.92, J = 5.6 Hz, for 3 as signals for the equatorial methyl groups). Observations concerning the furan proton are in accord with those made earlier (20, 21). I n the region 6 2.7-3.08, complex signals of area 4 appear that are attributed
196
JERZY T . WROBEL
to two protons in the furan ring (at C-4 and C-4') and to the two equatorial protons a t C-6 and C-6'. These assignments are made by analogy with the chemical shifts of the corresponding protons in 3. The spectrum of 43 also contains a well-defined AB pair of doublets centered a t 6 2.32 (J = 11.5 Hz) and attributed to the CH2-S group (compare with a singlet a t 6 2.67, W+ = 3 Hz, in the spectrum of 4 4 ) . By analogy to the studies on model compounds (24) the absorption of the thiomethylene group suggests an equatorial conformation of the CH2-S with respect to the quinolizidine ring.
0 44
The equatorial linkage of the sulfur atom to the second ring was based on evidence presented by LaLonde (25) for the equatorial character of the C-7-S linkage in thionuphlutine A, which in turn was shown to be identical with thiobinupharidine. All the evidence indicates structure 43 for thiobinupharidine. It has been confirmed by an X-ray crystal structure determination of thiobinupharidine dihydrobromide dihydrate. The observed bond lengths are in good agreement with the accepted values. The only bond that exceeds the average value is that between C-17' and C-7'. The alkaloid has a pseudo-twofold axis. The nonpolar character of the S-containing ring and the inequivalence of S and C-17' destroy this element of symmetry. LaLonde et al. (23)provided further evidence consistent with structure 43. The 100 MHz NMR spectrum of thiobinupharidine determined in benzene shows the two C-4 protons as two overlapping quartets both with splittings of 1.5 and 10 Hz. Such a splitting pattern may be ascribed to an axial (3-4 proton rather than to an equatorial one. Evidence for the stereochemistry of the C-1 and C-1' methyl group comes from the direction of the solvent-induced shift of the C-1 methyl group observed in the NMR spectrum. The C-7 axial methyl group in deoxynupharidine is shifted downfield by 4.2 Hz and the C-1 equatorial methyl is shifted upfield by 5.0 Hz when deuterochloroform is replaced
3.
197
by benzene. The same solvent change results in an upfield shift of 8 Hz for the methyl groups of 43. This demonstrates that both methyl groups in thiobinupharidine are equatorial. Extensive NMR studies allowed LaLonde et al. (23) to assign an equatorial sulfur bonded to the AB quinolizidine system and furthermore to suggest that the sulfur atom is involved in the reduction (NaBH, and NaBD,) of 6- and 6'-dihydroxyl derivatives of thiobinupharidine through a three-membered ring (25) (Eq. 11).
S '
\S
S
__f
A+\
OH
+ L A <
OH
(11)
's
"i"
D
A. C,, ALKALOIDS OF SULFOXIDE STRUCTURE To date, one alkaloid only of the sulfoxide type has been isolated from Nuphar buteum. On the basis of chemical and spectroscopic evidence, the alkaloid was shown by Wr6be1, MacLean, et al. (26)to be neothiobinupharidine sulfoxide (45) which was prepared from neothiobinupharidine by hydrogen peroxide oxidation. Reduction of 45 with
45
(C~OHCJNS~~S)
phosphorous trichloride led to neothiobinupharidine thus confirming the above structure. Neothiobinupharidine sulfoxide (45) was the object of extensive mass spectrometric studies (26). The results are given in Section IV.
198
JERZY
T.
WROBEL
B. C,, ALKALOIDS OP CARBINOLAMINE STRUCTURE

A number of C,, sulfur-containing alkaloids have hydroxyl or alkoxyl groups in the 6 position to the nitrogen atom (27-30). Compounds of that type of structure are listed in Table I1 (23, 26-34) (Compounds 2-1 0). Spectroscopic chemical and mass spectrometric studies (see Table I) led to the structures of a number of carbinolamines. Nuphleine (46) (C,,H,,N,O,S) was shown t o have two hydroxyl groups. Sodium borohydride as well as catalytic reduction yielded thiobinupharidine (43). Thus, nuphleine was shown to be a dihydroxy derivative of 43. Thionupharoline (47) (C,,H,,N203S) recognized first as a monohydroxy derivative of the C,,H,,N202S alkaloids (28) was recently proved by MacLean, Wrbbel, et al. (31) to be 6-hydroxythiobinupharidine, a compound identical with 6-hydroxythionuphlutine A isolated by LaLonde (23),who independently elucidated its structure. The alkaloid was isolated as its immonium ammonium diperchlorate, which revealed in the I R spectrum the presence of the
\
/
+/
band
at 6 . 0 2 ~ and R,N+H absorption a t 4 . 3 5 ~ The . immonium monoperchlorate showed Bohlmann bands a t 3 . 6 0 ~These . observations suggested the dual amine-hemiaminal character of the free base. The latter recovered from the perchlorate showed in its mass spectrum the highest mass fragment a t m/e 492 (M+-H,O). The I R spectrum revealed Bohlmann bands and absorption characteristics of the 3-fury1 group, whereas the NMR spectrum showed the presence of one proton exchangeable with D20. Reduction of 51 with sodium borohydride results in thiobinupharidine (43), and reduction with sodium borodeuteride gives thiobinupharidine-6-d,. Since the NMR spectrum displays a singlet a t 6 3.98 attributed to the proton H O C J N
/ \
, ato nitrogen
and to the hydroxyl group, the latter can only be located a t C-6 or C-6'. The location of the hydroxyl group a t the C-6 position was supported by NMR and MS studies of the thiobinupharidine-d, obtained by reduction of 51 with sodium borodeuteride. NMR spin decoupling experiments on the deuterated sample showed C-6' axial and C-6' equatorial protons at 6 1.41 and 3.16, resp and a C-6 axial proton a t 6 1.91. These findings demonstrate that the C-6 position was reduced stereospecifically with the introduction of an equatorial deuterium. Incorporation of the equatorial deuterium indicated that the hydroxyl
TABLE I C1, Nuphar ALKALOIDS AND THEIR PROPERTIES a Melting point ("C) Melting point of the salts ("C) Reference
w
2
b
9
Compound 7-Epideoxynupharidine(19) Nuphenine ( 2 0 ) (anhydronupharamine) 3-Epinuphamine ( 2 8 ) Nupharolidine (34) Nupharolutine (38) 6,7-Oxidodeoxynupharidine(39) 7 -Epinupharamine (epi-15)
a
Formula C15H23NO CI5Hz3NO Ci,Hzi"z C15H2,N02 C15H23N02 C3,H*2N20, c 1 asNO2
110 9&98 165-170
- 89
-23 (Hg) -41.5
HCl, 255-258
HCI, 240-245
- 105 -93
9, 10 11-1 4 16 17 18 19 Ila
Cf. Table I in Wr6bel (5).
tQ
0 0
TABLE I1 NATURALLY OOCURRINQc30 SULFUR-CONTAININQ ALKALOIDS AND THEIRPROPERTIES Melting point ("C) 240-242 Amorphous
Compound Neothiobinupharidine sulfoxide (45) Thionupharoline (47) (6-hydroxythiobinupharidine) 6-Hydroxythionuphlutine B (54) 6'-Hydroxythiobinupharidine (55) 6,W-Dih ydroxythiobinupharidine (6,6'-dihydroxythionuphlutineA) (52) 6,6'-Dihydroxythionuphlutine B (53) Nuphleine (46) Thionupharodioline (48) Ethoxythiobinupharidine (49) Diethoxythiobinupharidine (50)
a
Formula
an
Melting point of the salts ("C)
Reference
2HC104, 172-174 or (260-263), HC104, 240-243
+34
26 23, 28, 31-33 34 23, 34 23, 29, 31, 33 23, 29, 32, 34 27 30 30 30
r4
2
Y
2HC104, 216-220 2HC104, 22G228

-
- 69
Amorphous 156-158
+ 44.5
-
0.
2HC104, 225-226
~ H C ~ 270 O ~ , 2HC104, 230
Amorphous
Cf. Table I1 in Wr6bel ( 5 ) .
3.
20 1
group is located a t C-6, since the reduction a t C-6' results in incorporation of an axial deuterium atom. The stereochemistry of the reduction was established through studies on 6,6'-dihydroxythiobinupharidine and on model compounds (23).I n addition, it was pointed out (23, 30) that the fragments of m/e 228 (37-3970) and 176 (37-10070) observed in the spectra of 6,6'-dihydroxy Nuphar C,, alkaloids, although present in the spectra of thio- and neothiobinupharidine, are of very low intensity. The appearance in the mass spectrum of 6-hydroxythiobinupharidine of these fragments with intermediate intensities (62 and goy0) seems t o confirm the presence of one hydroxyl group a t the 6- or 6'position in 51.
p
Me I
, ' ' \
mle 228
m/e 178
MacLean, Wr6be1, et al. (31) presented further experimental data, which led to structure 51 for thionupharoline (47). Of special value were extensive NMR studies a t 220 MHz, which very clearly recognized the following protons (in CDC1,); 6 2.26 (OH exchangeable with D,O), 2.89 ( l H , C-4'), 2.92 ( l H , C-6 H eq), 3.70 ( l H , C-4), and 3.97 ( l H , C-6 sharpens on addition of D,O). The 220 MHz NMR spectrum of thiobinupharidine-6d (obtained from the reduction of 47 with sodium borodeuteride) allowed the protons a t C-4 (4') and C-6) (6') t o be more precisely recognized. The following data were obtained in CDC1,: 6 1.45 (C-6' H,,), 1.70 (broad singlet superimposed on envelope C-6 H,,), 2.79 (0.55, C-6 H,,),
Me
51
202
2.93 (C-4 H, C-4 H), 2.93 (C-6 Heq);and in CsD,: 1.40 (C-6 H,,), 1.93 (0.32 H, C-6 H,,), 2.80 (2H, C-4 Ha, and C-4 H,,), 3.10 (0.62 H, C-6 Heq),3.18 (1.04 H, C-6 Heq).
6,6-Dihydroxythiobinupharidine (6,6-dihydroxythionuphlutine A) (52) (C3,H4,N2O4S) was first isolated by LaLonde et al. (89) from
17
52
Nuphar luteum subsp. macrophyllum (23, 31, 33). The NMR spectrum a t 220 MHz (31) showed signals a t 6 3.98 ( l H , C-6 Heq) and a t 4.24 ( l H , C-6 Heq) in CDCl,. In C6D6 + D,O solution, these protons appeared a t 6 4.23 (1H, C-6 Heq) and 4.35 ( l H , C-6 Heq). An axial configuration was assigned t o the hydroxyl groups a t C-6 and C-6. Thionupharodioline (48) C,,H,,N,O,S is isomeric with 52. Wr6bel et al. (30)suggested that the two alkaloids differ in the configuration a t C-6 and C-6. It was isolated from Nuphar luteum (Polish origin) and is a crystalline solid of mp 156-158C. Both potassium borohydride and catalytic reductions resulted in thiobinupharidine. The strong hydrogen bonding observed in the IR spectrum and the very low intensities of the Bohlmann bands indicate equatorial configurations for OH groups a t C-6 and C-6. The proposed structure (48) is shown below.
Me
48
3.
203
Ethoxythiobinupharidine (49) and diethoxythiobinupharidine (50) were isolated from Nuphar luteum (30).Their structures were based on on I R , NMR, and mass spectrometry studies as well as on the product of reduction with potassium borohydride, which in both cases gave thiobinupharidine (43). The configuration of the ethoxyl groups has not yet been established. Since no ethylating agents were used during the
49
50
R1 = OEt, R, = H R, = R, = O E t
or
R, = H, R,
= O Et
isolation procedure of 49 and 50, the ethoxy group could not have been introduced during the process (30). The structure of 6,6'-dihydroxythionuphlutine B (53) (C,,H,,N,O,S) isolated by LaLonde (29) was recognized as isomeric with those of both thio- and neothiobinupharidine (23,32)dihydroxy- derivatives. On the
53 54
R,,R, = H,OH; R , , R4 = H, OH R1, R, = H,OH; R , = R, = H
basis of extensive NMR studies of 53 and of its deuterated reduction products, it was possible to show that this alkaloid contains an axial sulfur atom attached to the AB quinolizidine system and an equatorial -CH2-Sgroup attached to the A'B' quinolizidine system.
204
JERZY T .WR~BEL
6-Hydroxythionuphlutine B (54) is another monohemiaminal isolated and investigated by LaLonde (34).The evidence for the position of OH group was based on NMR, mass, and CD data. The significant difference in the chemical shifts of the carbinyl hemiaminal protons were observed (for C-6 and C-S, 4.08 and 3.94 6, respectively). The mass spectrometry of thiaspiran singly labeled by deuterium showed a mle 178 to m/e 179 shift. It was found that the singly deuterated thiaspirans that were labeled at C-6 resulted in m/e 178 shifting to 179 by goyo, and those labeled a t C-6 resulted in a 10% shift only. The CD of C-6 hemiaminals in acid solution showed positive bands but those with C-6 hydroxy substitution showed both positive and negative bands. These results allowed LaLonde (34) to establish the structure of 6-hydroxythiobinupharidine(55) (C,,H,,N,03S).
IV. Mass Spectrometry

Considerable progress has been made in the mass spectrometry of Nuphar alkaloids C,, and C3,,. MacLean and Wr6bel gave the basic mechanism of the fragmentation of several types of Nuphar alkaloids using high-resolution mass spectrometry. The mass spectra of following C,, alkaloids were recorded: deoxynupharidine (3), nupharidine (l), castoramine (34), and nupharolutine (38)(see Scheme 1). The mass
Me
Me
C SCHEME 1
3.
205
spectrum of deoxynupharidine was first reported in 1964 (35). High resolution studies confirmed the composition assigned to the intense ions in the previous work (35) and allowed the composition of less intense ions to be determined. The fragmentation involves the four bonds in position /3 to nitrogen, to yield molecular ions A, B, C, D. The ion C either splits further into homologous ions a, b, c or undergoes the retro Diels-Alder reaction to yield ions d and e. Ions D and C can also result in ions f and g. Another path of decomposition of 3 consists in a loss of the furan ring and formation of the h ion (Scheme 2). The formation of the major ions in the spectrum of 3 is shown in Scheme 3. All the major ions a t m/e = 136 (j), 98 (k), 97 (l), 94 (m), and 55 (n) originate in the ion C. When fragmentation proceeds with hydrogen transfer, as shown in route 3d (there is no evidence that the hydrogen actually originates from site C-2, as schematically shown), the resulting ion is k a t m/e 98. The recent labeling studies (29) are in accord with the structure proposed for these ions. Further fragmentation of the ion j, a t m/e 136, has also been observed (cf. Scheme 3 routes 3e and 3f). Fragmentation of castoramine (34) is similar to that of deoxynupharidine, as shown by parallel Schemes 1-3. The spectrum of 34 shows ions absent in the spectrum of 3, owing to the presence of the hydroxyl group, as also shown in Schemes 1-3. Recent work (26) on the spectra of neothiobinupharidine (44)and related systems showed that the dimeric compounds have many ions in their spectra whose formation may be interpreted in terms of the schemes suggested above. The fact that the fragmentation of 3 and 34 and many of the fragmentations of 44 may be interpreted through Schemes 2 and 3 lends credibility to them. The hydroxyl group present in 34 leads to new ions in its spectrum, which are absent in the spectrum of 3. Thus, a strong ion a t m/e 96 can be ascribed to 34K-H20;an ion a t m/e 164 to 34K-H20 and the ions a t m/e 218 and 219 to the loss of CH20 and CH20H from the molecule as shown in Scheme 4. The spectrum of nupharolutine (38) has many features in common with that of castoramine, but it is distinctly different from that of nupharidine. The differences between the spectra of 38 and 34 are compatible with the structural differences. Thus, the loss of Me and OH is favored more in 38 than in 34 as would the formation of ion f. The spectra bear this out. It should be noted that the loss of H 2 0 from m/e 114 to form m/e 96 is more pronounced in 38, the tertiary alcohol, than it is in 34,the primary alcohol.
206
b
m/e 190 (ClzH16NO) m/e 204 (C12H16NOz)
3 38 and 34
yc
d
m/e 204 (Cl3H1,NO) m/e 220 (Cl,Hl,NOa)
m/e 178 (CllHl,NO) mle 192 (C1iHiiN"a)
J ? '
P
e
Me
h
3 38 and 34
3, 38,and 34 m/e 162 (Cl,H12NO)
3, 38, and 34 m/e 148 (C,H,,,NO)
mje 166 (C11HaoN) m/e 182 (ClIHa0NO)
C'I
( J Q R z
H transfer
I""';z
Me
C
3, 38, and 34 n / e 178 (C,,H,,NO)
SCHEME 2
3.
207
Route 3b
d
0
2
0
NQR,
K.1
j
3. 38. and 34
V
m/e 136 (CsH,,O)
3 38 and 34
m/e 97 (C,H,,N) m/e 113 (C&,,NO)
3, 38, and 34 mle 55 (C,H,N)
k
3 38.34
m/e 98 (C,H,,N) m/e 114 (C.H,,NO)
\*
3, 38, and 14
m/e 136 (C,H,,O)

r n
3, 38, and 34 m/e 94 (C,H,O)
SCEEME 3
208
JERZY T .WR~BEL
mle 219
mle 218
SCHEME4
The spectrum of nupharidine (l), like those of other N-oxides, shows the loss of oxygen and OH [peaks a t rn/e 232 and 231 ( 3 6 ) ] .The peak at m/e 220 does not result from loss of an ethyl fragment but from loss of CHO, a fragmentation characteristic of furans. I n Scheme 5 , suggestions are made for the derivation of the major ion a t m/e 114 and related fragments based upon a determination of their compositions by high resolution studies (18). MacLean and Wr6bel (26)have also suggested a mechanism of fragmentation of C,, alkaloids, such as neothiobinupharidine (44),thiobinupharidine (43), and neothiobinupharidine sulfoxide (45).Spectra of these compounds show a number of ions identical with those shown in Schemes 1-3. Fragmentation of neothiobinupharidine (44) and of related systems
Me
Me
Me
3.
209
(26),as well as of 54, can also be interpreted in terms of Schemes 2-3. This lends credibility to the suggested reaction paths. Ions a t m/e 461 and 447 have no counterpart in the spectrum of 3, and they owe their origin to the loss of SH and CH,SH, respectively, from the molecular ion. An ion at mfe 359 formed by loss of C,H,,O
Me
44
from the molecular ion may be represented as in Scheme 6. The analogous ion in 3 appears a t m/e 98. If hydrogen transfer does not occur and the charge remains with the furan moiety an ion a t mle 136 results with the same mass and composition as in the spectrum of 3. The spectrum shows ions a t mle 230, 178, 107, and 94 besides that at mle 136. The ions at mfe 94 and 107, which also appear in 3 can be
Me
H transfer
/
+
Me I
m/e 359, C,,H,,N,OS
SCHEME 6
210
formed from 44 in a similar way. The structure of the ion a t m/e 230 (C,,H,,NO) is formulated and derived as shown in Scheme 7. If a hydrogen is transferred t o the sulfur-containing fragment and charge is retained on this fragment, the ion at m/e 264 is observed (C15H22NOS). The most intense ion of the spectrum a t m/e 178 corresponds in
Me
44
M + = 494
mle 231
Me
Me
m/e
264, C1,H,,NOS
SCHEME 7
m/e 230,
C,,H,,NO
composition t o C,,H,,NO. Its derivation is shown in Scheme 8. Charge is also carried by the residual fragment, for a peak of low intensity is also present a t m/e 316 (CISH,,NOS). An ion of m/e 178 is present in 3, but its intensity is relatively weak. I n their study of the reduction products of the thionuphlutines, LaLonde et al. (29) came t o the same conclusion regarding the derivation of the ions a t m/e 178 and 230. New fragments due t o the oxygen function on sulfur appear in the spectrum of 45, which has a sulfoxide structure but the general pathway of fragmentation remains unchanged. The mass spectrum of 45 shows losses of SOH and CH,SO from the molecular ion at m/e 461 and 447 paralleling the losses of SH and CH,SH from neothiobinupharidine. An intense peak a t m/e 493 corresponds t o the loss of OH. The rest of the spectrum of 45 is similar t o that of neothiobinupharidine. Thus, the peaks a t m/e 230, 178, 136,
3.
211
44
M + = 494
$ + +
*
I
Me
1
\CH,
Me
107, and 94 are all present and have composition identical with those found in the spectrum of 44.Ions of low intensity are also present at m/e 280 (C,,H,,NO,S), 262 (280-HZO), 375 (C,,H,,N,O,S), and (357-H20). The mle 280 ion is cognate to mle 230, while m/e 375 is cognate to mle 136-H.
V. Total Synthesis of C,, Nuphar Alkaloids

Racemic forms of nupharamine (15) and 3-epinupharamine (epi-15) were synthesized by Szychowski et al. (37) from @-acetylfuran (56) (Eq. 12). The Claisen type condensation of 56 with ethyl formate resulted in ketoenolate 57, which with /I-aminocrotonate yielded the furylpyridine derivative (58) (Eq. 13).
C-CHSHONe
WEtl0
56
(12)
57
212
I
NH2
57
Me-C-CH-COzEt
benzene/AcOH
,
58
CO,Et Me
The OH group in compound 59, obtained by LAH reduction of 58, was replaced with hydrogen resulting in 60. This compound in the presence of NaNH,/liquid NH, reacted with ,t?-methallyI chloride. Compound 61 had the required carbon skeleton; the NMR proton characteristics are given in 61. Nupharamine and 3-epinupharamine
7.3803)
2.31
1.84
(2M.92 H ~
r ~ N ^ . H 2 - c H 2 - c ~ ~ 2 I
2.92 2.5 (10; 5) (10: 5) 8.05
Me
4.78
(2)7.5H
61
were prepared from 61 in two steps. The first consisted in the selective and stereospecific hydrogenation of 61 with sodium/ethanol in xylene resulting in a mixture of epimers 62 on carbon C-3 with both equatorial: fury1 group and the side chain. Compound 62 was hydrated with formic acid (catalytic amount of HCIO,) ; subsequent chromatography on alumina resulted in two racemates of ( )-nupharamine and ( & )-3epinupharamine.
b:.*
Me
NH /
6%
3.
213
VI. Biosynthesis
The sesquiterpenoid structure of Nuphar alkaloids suggests that their carbon skeleton may be derived from mevalonic acid, but the biosynthesis of the furan and spirotetrahydrothiophene rings can not be clearly predicted. Preliminary evidence indicates that label from [3,4-14C]mevalonateenters thiobinupharidine (38).Partial degradation was carried out, but the results remain inconclusive, since their interpretation was based on a structure of thiobinupharidine that was incorrect. Incorporation of [1 ,5-14C]cadaverine (38) was presumably indirect.
REFERENCES
1. Y. Arata, S. Yasuda, and K. Yamanouchi, Chem. Pharm. Bull. 16, 2074 (1968). 2. Y. Arata and K. Yamanouchi, Yakugaku Zasshi 91,476 (1971). 3. R. T. LaLonde, E. Auer, C. F. Wong, and V. P. Muralidharan, J. Am. Chem. SOC. 93, 2501 (1971). 4. R. T. LaLonde, J. T. Wooleveler, E. Auer, and C . F. Wong, Tet. Lett. 1503 (1972). 5. J. T. Wr6be1, in The Alkaloids (R. H. F. Manske, ed.), Vol. IX, p. 450, 1967. Academic Press, New York. 6. D. C. Aldridge, J. J. Armstrong, R. N. Speake, and W. B. Turner, J . Chem. SOC. 1667 (1967). 7. C. F. Wong, E. Auer, and R. T. LaLonde, J . Org. Chem. 35, 517 (1970). 8. K. Oda and H. Koyama, J . Chem. SOC. 1450 (1970). 9. C. F. Wong and R. T. LaLonde, Phytochemistry 9, 2417 (1970). 10. C. F. Wong and R. T. LaLonde, Phytochemistry 9, 659 (1970). 10a. T. M. Moynehan, K. Schofield, R. A. Y. Jones, and A. R. Katritzky,J. ChemSoc. 2637 (1962). 11. R. Barchet and T. P. Forrest, Tet. Lett. 4229 (1965). lla. T. P. Forrest and S. Ray, Can. J . Chem. 49, 1774 (1971). 12. C. Y. Chen and R. J. W. LeFevre, J . Chem. SOC. 3467 (1965). 13. Y. Arata, T. Ohashi, M. Yonemitsu, and S. Yasuda, Yakugaku Zmshi 87, 1094 (1967). 14. Y. Arata end T. Ohashi, Chem. Pharm.Bull. 13, 1247 (1965). 15. Y. Arata and T. Ohashi, Chem. Pharm. Bull. 13, 1365 (1965). . LaLonde, Phytochemktry 9,1851 (1970). 16. C. F. Wong and R. T 17. J. T. Wr6bel and A. Iwanow, Rocz. Chem. 43, 997 (1969). 18. J. T. Wrbbel, A. Iwanow, C. Braeckman-Danheux, T. I. Martin, and D. B. MacLean, Can. J . Chem. 50, 1831 (1972). 19. R. T. LaLonde, C. F. Wong, and K. C . Das, J. Am. Chem. SOC. 94, 8522 (1972). 20. 0. Achmatowicz and J. T. Wr6be1, Tet. Lett. 129 (1964). 21. G. I. Birnbaum, Acta Crystabgr. 23, 526 (1967). 22. J. T. Wrbbel, B. Bobeszko, T. I. Martin, D. B. MacLeen, N. Krishnamachari, and C. Calvo, Can. J . Chem. 51, 2810 (1973). 23. R. T. LaLonde, C. F. Wong, and K. C . Das, J . Am. Chem. SOC. 95, 6342 (1973). 24. R. T. LaLonde, C. F. Wong, and H. G . Howell, J . Org. Chem. 36, 3703 (1971).
214
25. R. T. LaLonde, U.S.C.F.S.T.I., P.B. Rep. PB-192 810 (1970); C A 74, 39208b (1971). 26. J. T. Wrbbel, A. Iwanow, J. Szychowski, J. Poplawski, C. K.Yu, T. I. Martin, and D. B. MacLean, Can. J. Chem. 50, 1968 (1972). 27. T. N. Ilinskaya, A. D. Kuzovkov, and T. G. Monachova, Khim. Prir. Soedin., Akad. Nauk. Uz.SSR 178 (1967); CA 67, 117029r (1967). 28. J. T. Wrbbel, Rocz. Chem. 44, 457 (1970). 29. R. T. LaLonde, C. F. Wong, and W. P. Cullen, Tet. Lett. 4477 (1970). 30. J. T. Wr6be1, M. Gielzyhska, A. Iwanow, and W. Starzec, Bull. Acad. Pol. Sci., Ser. Sci. Chim. 21, 543 (1973). 31. T. I. Martin, D. B. MacLean, J. T. Wr6be1, A. Iwanow, and W. Starzec, Can. J. Chem. 52, 2705 (1974). 32. C . F. Wong and R. T. LaLonde, J. Org. Chem. 38, 3225 (1973). 33. R. T. LaLonde, C. F. Wong, and K. C. Das, Can. J. Chem. 52, 2714 (1974). 34. R. T. LaLonde, C. F. Wong, and K. C. Das, J. Org. Chem. 39, 2892 (1974). 35. 0. Achmatowicz, H. Banaszek, G. Spiteller, and J. T. Wr6be1, Tet. Lett. 927 (1964). 218 (1966). 36. R. Grigg and B. G. Odell, J. Chem. SOC. 37. J. Szyohowski, J. T. Wrbbel, and A. Leniewski, Bull. Acad. Pol. SCi., Ser. Sci. Chem. 22, 383 (1974). 38. H. R. Schutte and J. Lehfeldt, Arch. P h m . (Weinheim, Ger.) 298, 461 (1965).
-CHAPTER
THE CELASTRACEAE ALKALOIDS

ROGER M. S ~ H
School of Natural Resources The University of the South Pacijk Suva, Fiji
I. Introduction ....................................................... 1 1 . Occurrence and Isolation ............................................ 1 1 1 . Structures of Esters of Nicotinic Acid ................................. A. Esters of Cl5HZ6O5Polyols ....................................... B. Esters of C15Hz606Polyols ....................................... C. Esters of Cl5HZ6O7 Polyols ....................................... D. Esters of Cl5HZ6Os Polyols ....................................... IV. Structures of Diesters of Substituted Nicotinic Acids.. .................. A. Structures of the Diacids ......................................... B. Esters of Cl5HZ4O9 Ketopolyol .................................... C. Esters of Cl5HZ4Ol0 Ketopolyol.. .................................. D. Esters of C15H260,, Polyols.. ..................................... V. Structures of Related Sesquiterpene Esters and Polyols.. ................ VI. Biosynthesis ....................................................... VII. Biological Properties ................................................ References .........................................................
215 216 219 219 224 224 226 227 227 229 231 239 241 245 246 246
I. Introduction
I n 1970 the structures of the nicotinoyl alkaloids maytoline (I)*and maytine (2) from Maytenus ovatus Loes. (Celastraceae) were reported as prototypes of a new family of alkaloids ( I ) . Subsequently, the closely related structures or partial structure for twenty-two further alkaloids from a number of different species in the family Celastraceae have been elucidated. They all contain either a nicotinate or substituted n k o tinate group and are polyesters of hydroxy derivatives of dihydroagarofuran (3).7 The other ester groups can include benzoate, acetate, and 3-furoate. Many of these alkaloids had been isolated previously,
* All the sesquiterpene polyols have been aasumed to have the same absolute stereochemistry as bromoacetylneoevonine (SO), the only member of the series to have been fully elucidated. t The sesquiterpene nucleus is numbered in accordance with Chemical Abetracts.
216
ROGER M. SMITH
but their structures had not been fully elucidated, although in most cases the presence of a C,, nucleus and a nicotinic acid group had been recognized. A number of closelyrelatednonbasic sesquiterpene polyesters and free polyols have also been reported. This review covers the isolation and chemistry of the nicotinoyl polyester alkaloids reported up to late-1975. Previous reviews of the pyridine alkaloids (2, 3 ) have included the substituted nicotinic acids, but the full structures of the alkaloids were not then known. More general reviews of members of this family have considered the constituents including alkaloids of Khat (Catha edulis Forskal) ( 4 , 5 ) and the pharmacology of alkaloids and terpenes from the Celastraceae and Hippocrateaceae ( 6 ) .
CH3
1
Maytoline R = OH Meytine R =H
11. Occurrence and Isolation

The first report of the presence of highly oxygenated C, compounds in the Celastraceae was during a study in 1938 of the seed oil of Celastrus paniculatus Willd. (7). Hydrolysis of a methanol-soluble fraction yielded formic, acetic, and benzoic acids, and a tetraol (c15&,@5). Nicotinic acid would, however, not have been detected. The first Celastraceae alkaloids, base A (C,,H,,NO,,), base B (C27H35N012), and base C (C,,H,,NO,,), were isolated in 1947 from the spindle tree Euonymus (or Evonymus) europaeus L., which is used in folk medicine. They were thought to be tetra-, tri-, and pentaacetates, respectively, and on acetylation both A and B were converted to base C (8). Because of an interest in their pharmaceutical activity, the ripe seeds were later reexamined by Pailer and Libiseller in 1961 ( 9 ) , who isolated evonine (base C), the principal alkaloid. They showed that the basic function of evonine was evoninic acid (4), a substituted nicotinic
4.
CELASTRACEAE ALKALOIDS
217
acid, present as its diester of an unidentified polyhydroxy nucleus (10).TLC examination showed the presence of other basic (C15Hz6010) components, but these were not isolated. Similarities were recognized between the partial structure of evonine and five partially characterized alkaloids that had been isolated between 1950 and 1 9 5 3 from the thunder god vine (Tripterygium wilfordii Hook.) by Acree and Haller (11)and by Beroza (12-15) using a combination of partition chromatography and countercurrent distribution (16,17). These alkaloids contained a common polyol nucleus (C15H26010), which was esterified with a substituted nicotinic acid, either wilfordic (6) or hydroxywilfordic acid ( 7 ) (18),acetic acid, and either 3-furoic or benzoic acid (14, 15).
m ;
N
&&R YH3
H3C H 4 Evoninic acid R = CO,H R = OH 5
A A
cICozH
N
CHz-CHZ4(CH3)-CO2H R
6 7
Wilfordic acid R = H Hydroxywilfordic acid R = OH
The stimulating effect of Khat, Catha edulis another member of the Celastraceae, had been widely studied, and the major alkaloidal constituents have been found t o be norpseudoephedrine and related compounds ( 4 , 5 ) . During a search in 1 9 6 4 for further alkaloids, a weakly basic compound, cathidine D (C,,H,,NO,,) was isolated (19). Analysis showed it to be a polyester of acetic, benzoic, and nicotinic acids and an undefined polyol (C,,H,,06), and it was suggested that it could be related to the other Celastraceae nicotinoyl alkaloids. For some years, no further work in this area was reported, until, in 1970, Kupchan, Smith, and Bryan, investigating Maytenus ovatus for tumor inhibitory compounds, isolated the weakly basic but inactive alkaloids maytoline (1) and maytine (2) and determined their full structure and relative stereochemistry by NMR spectroscopy and X-ray crystallography (1,ZO).These compounds were based on a hydroxylated tricyclic dihydroagarofuran nucleus, and it was suggested that this was structurally related to the C,, polyols of the Euonymus and Tripterygium a 1kaloids. Following this report, a series of papers appeared on the alkaloids of Euonymus Sieboldianus Blume by Yamada and his co-workers, who reported the isolation and structures of a series of related alkaloids including evonine (21-24) and by X-ray crystallography determined their absolute stereochemistry (25) and confirmed their relationship to maytoline.
218
ROGER M. SMITH
TABLE I OCCURRENCE AND ISOLATION OF CELASTRACEAE ALKALOIDS Alkaloid (synonyms) Alatamine Cathidine D Celapagine Celapanigine Celapanine 2-Deacetylevonine 2,6-Dideacetylevonine Euonine Euonymine Evonine (alkaloid C) Plant
Part
Reference 26 19, 27 28 28, 29 28, 29 30 30 31 26 23 26 8,9,32-35 21 32, 34, 36 8, 33 36, 37 31 33 1, 38 38 1, 38 23 8, 33, 34 23 26 11,12 13 39 12 13 15
Evonoline (4-deoxyevonine) Evozine (alkaloid B) Isoevonine (evonimine) Isoevorine (alkaloid D) Maytine Maytolidine Maytoline Neoeuonymine Neoevonine (evorine, alkaloid A) Wilfordine Wilforgine Wilforine
Euonymua alatusa Catha edulis Celastrus paniculatus paniculatus paniculatus Euonymus europaeus europaeus Sieboldianus alatus Sieboldianus alatus europaeus Sieboldianus europaeus europaeus europaeus Sieboldianus europaeus Maytenus ovatus ovatus watm Euonyrnua Sieboldianus europaeus Sieboldianus alatus Tripterygium wilfordii wilfordii Maytenus senegalensis' Tripterygium wilfordii wilfordii wilfordii
Leaves Seeds Leaves Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Roots Roots Stems and roots Roots Roots Roots
Wilforgine Wilforzine
E . alatus forma striatus (Thunb.) Makino. Known subsequently as M . arbutifolfolia (Hochst. ex A. Rich.) R. Wilczek ( 4 1 )andnow as M . sewata (Hochst. ex A. Rich.) R. Wilczek (persona1communication from Professor S. M. Kupchan). M . senegalem's (Lam.) Exell.
4. CELASTRACEAE ALKALOIDS
219
Subsequent investigations of these and other members of the family Celastraceae have yielded further alkaloids (see Table I) ( 1 , 8, 9 , 11-13, 15, 19, 21, 23, 26-41). The nature of the sesquiterpene nucleus and ester functions is known in each case, but for some of the alkaloids, the position of the acyl groups have not yet been determined. The alkaloids can be grouped into those containing an unsubstituted nicotinate group and into the generally larger and more complex compounds in which the basic function is a substituted nicotinate group. Many studies have reported the presence of alkaloids in these and other members of the Celastraceae by TLC spot tests or as crude basic extracts. However, as well as the nicotinoyl alkaloids, a wide range of other alkaloids have been isolated, more than one type frequently occurring in the same plant. Maytenus ovatus, in addition to maytine and maytoline, has yielded the antitumor ansa macrolide maytansine (40) from the seeds and the spermidine alkaloid celacinnine from the twigs (41). Maytenus Chuchuhuashu Raymond-Hamet and Colas has given an open chain spermidine alkaloid maytenine (42)and Maytenus buchanii has yielded a further ansa macrolide (43).A series of peptide alkaloids was found in Euonymus europaeus following TLC analysis (44) and Catha edulis has been reported to contain a number of alkaloids related to norpseudoephedrine (45). I n addition, a number of nonbasic polyesters and polyalcohols have been isolated with sesquiterpene nucleii similar or identical with those found in the alkaloids (see Section V).
III. Structures of Esters of Nicotinic Acid

Seven alkaloids have been isolated in which the basic function is a nicotinate group (Table 11). Similarities in the NMR spectra have suggested that in each case the nicotinate group is at C-9.
A. ESTERS OF C,,H,,O,
1. Celapanine
Polyols
Celapanine (8) was isolated together with a neutral diester malkangunin (see Section V), and much of its structure was derived by their interrelation ( 2 8 , 2 9 , 4 6 ) . The mass spectrum of celapanine (C,oH,,NO,o) (mle 569) confirmed the molecular formula and suggested the presence of nicotinate (m/e 106 and 7 8 ) and 3-furoate (m/e 95) groups. These conclusions were in agreement with bands in the NMR and UV spectra. The NMR spectrum (Table 111) also contained signals for two acetyl
220
ROGER 1 . SMITH
4.
22 1
groups (6 1.68,2.12), four tertiary and one secondary methyl groups, and coupled signals at 6 2.60, 5.73, and 5.4, which were assigned to the grouping -CH,-CHOAcyl-CHOAcyl-. The alkaloid is therefore, a tetraester of a C,,H,,O, nucleus, celapanol. As the infrared spectrum, vmaX 1740,1730,1590,1560cm-l, contained no bands for a free hydroxyl or ketonic carbonyl groups, the remaining oxygen must be an ether
Celapanine Celapano1 Celapanigine 11 Celapagine

8
9 10
Ac
Fur
Ac Nic
H Ac Bz Ac Bz
H Ac Nic H Nic
Bz = benzoyl Nic = nicotinoyl

Fur = 3-furoyl
group. Dehydrogenation of 8 yielded eudalene (12),which was also obtained from the diester malkangunin (13)(28, 46). Comparison of the NMR spectrum of 8 with that of malkagunin suggested that the sesquiterpene nucleus in both cases contained similar tricyclic dihydroagarofuran skeletons, 9 and 14, respectively. One acetate group was positioned a t C-1 in 8 as the high-field position (6 1.68) was considered to be due to interaction with a nicotinate group at C-9. A similar relationship had been previously reported in maytoline (1) (I).The 3-furoyl group was placed a t C-6 as in the related alkaloid, celapanigine (lo), it is the position of a benzoyl group. The second acetate group was assigned to C-8 from the NMR spectrum. The stereochemistry of the ring system and substituents was based by Wagner and his co-workers on the structural assignments in malkangunin (13)(46). A spin-spin coupling between the protons at C-8
222
ROGER M. SMITH
TABLE lH-NMR SPECTRA OF CELASTRACEAE -oms
Alkaloid Celapanine (8) hlapanigine (10) Celapagine (11) Cathidine D (17) Maytine (2)
c-1
~
c-2
-b
c-3
c-4 2.25 mc 2.43 mc 2.44 m
C-6 5.4OC 5.62 dC 5.48 s
c-7 2.60 dc (3) 2.66 d c (3) 2.66 d C (3)
5.49 dd (10,5 )
5.5 me
4
-b
5.57 m
3.70 d (3.5)
6.00 d (3.5) 5.59 d (3.5) 5.91 d (3.5)
5.75 m 5.47 m
6.13 s
Maytoline (1)
5.60 t (3.5) 5.42 t (3.5)
3.60 d (3.5)
6.16
E I
Maytolidine (23)
5.84 d (3.5)
4.90 d (3.5)
6.23 s
a Spectra, run on solutions in CDCI,. Chemical shifts are in parts per million relative to tetramethyl silane (TMS). Figures in parentheses are couplings in Hertz. Bands were present as appropriate for nicotinate, benzoate, and furoate protons.
and C-9 of 7 Hz in the spectrum of 13 was assigned to a trans-diaxial system by andogy with dihydroxycyclohexanes and that between C-S and C-7 of 3 Hz to an axial-equatorial system. In 8 similar couplings (Table 1 1 1 ) led to the assignment of the C-8 and C-9 ester groups as diequatorial (28,46)[figure 7 in Wagner et al. (46)is incorrectly drawn]. From the coupling of the C-1 proton (J = 10, 5 Hz), it was deduced to be axial and hence the C-1 ester was equatorial. The negligible C-6, C-7 proton coupling places these protons axial-equatorial. However, a second group, den Hertog and his co-workers,who have studied the sesquiterpene nucleus malkanguniol derived from malkangunin have assigned the relative stereochemistry 16 rather than 14 on the basis of 'H and 13C NMR spectra (47,48) and on an X-ray crystallographic analysis (49).Thus, based on their formula, malkangunin would contain a C-8 axial, C-9 equatorial system (15) for which the
I11 C O N T ~ ~ I NA GNICOTINATE GROUP"
C-8 5.73 ddc (397) 5.70 ddc (3, 7) 4.66 ddc (39 7) c-9 5.4 d o (7) 5.36 d o c-12 1.59 s 1.61 s 1.60 s C-13 1.42 s 1.45 8 1.44 s C-14 1.01 d (7) 1.04 d (3-15 1.42 s 1.49 s 1.38 s
223
OAc
1.68 2.12 1.67 1.92 1.64
Reference
46 46 46
(7) 5.30 d c
(7)
(7)
1.01 d (7)
C-Methyl
5.75 m 5.47 m
1.40(3H), 1.54(6H), 1.66(3H) 1.51(6H), 1.56(3H)
5.01 s 4.39, 4.93d (13)
5.49 bd (7.5)
1.54(6H) 1.61(3H)
4.40, 4.96d (13)
5.52 bd (7.5)
1.55(3H), 1.59(3H), 1.61(3H)
4.43, 4.90d (13)
1.66 2.12 1.60 2.09 2.10 2.26 1.66 2.15 2.18 2.30 1.64 2.14 2.30 2.34
27
1, 38
1, 38
38
Unresolved multiplet 1.4-2.2 ppm. Position determined by spin-spin decoupling. AB quartet.
coupling of 7 Hz seems more appropriate. Examples elsewhere in this series of alkaloids have found J 8 , gax,eq = 6 Hz; ax,ax = 10 Hz (50). This group also isolated polyalcohol B to which they assigned structure 67 identical with celapanol (9). However, in this compound J 8 , g= 10 Hz and J,,8 = 3 Hz, in contrast with the values for the alkaloids.
2. Celapanigine and Celapagine
The spectra of celapanigine (10) (C32H3,N09)and celapagine (11) (C30H,,N08) were very similar to those of celapanine, except that instead of the bands assigned to the 3-furoyl group, there were signals characteristic of benzoate (mle 105 and 77) (28, 29, 46); 10 contained two acetyl groups ( 6 1.92, 1.67, NMR spectroscopy) but 1 1 only one,
224
ROGER M. SMITH
?H:
9R'
8R
O H ! OR'
R2
H3C
13 14
CH3 CH3
HSC
15 16
CH3 CH3
R ' = Bz,R2 = AC R'= R2 = H
R ' = Bz,R2 = AC R ' = R2 = H
which from its chemical shift (8 1.64) was assigned to C-1 due to the influence of a C-9 nicotinate group. The free hydroxyl group in 11 was secondary (-CHOH 6 4.66 dd, J = 7, 3 Hz) and from decoupling studies was assigned to C-8 (J8,9= 7 Hz, J,,8 = 3 Hz). The remaining ester function, the benzoate group, must be a t C-6. Compound 10 was thus based on the same polyol (9) as celapanine but contained a 6benzoate group instead of a furoate group, 11 being the corresponding 8-deacetyl compound. The stereochemical assignments were based on the same arguments as those for celapanine.
B. ESTERS OF C,,H,,06
POLYOLS
Although a number of pentaols have been isolated from hydrolyzates of Celmtrus paniculatus (Section V), so far no corresponding alkaloids have been reported.
C. ESTERS OF Cl5HZ6O7 POLYOLS

1. Cathidine D
Analysis and mass spectroscopy of cathidine D (17) confirmed the molecular weight of this weakly basic alkaloid from Catha edulis. Hydrolysis yielded nicotinic acid, benzoic acid, and 2 mole equivalents of acetic acid. Two of the remaining oxygen functions were assigned to a vicinal diol from the IR spectrum ( v , , , 3565, 3480 cm-l unchanged on dilution). The formation of a monoacetate and NMR spectra suggested that one hydroxyl was secondary and the other tertiary. This assignment was confirmed on treatment with lead tetraacetate, which cleaved
225
the diol quantitatively t o give a ketoaldehyde. Cathidine was thus a tetraester of the C,,H,,O, hexaol, cathol (19). Subsequent reexamination of the structural studies and comparison of the NMR spectrum with that of maytoline and maytine (Table 111) suggested that cathidine D contained the same C-1 to C-3 system as maytoline but lacked an ester function at C-6. As in maytine, the C-1 acetate group (6 1.66) apparently interacted with a C-9 nicotinate group. However, it was not possible t o distinguish between the possible positions for the benzoate and the second acetate groups. Cathidine was thus assigned the partial structure 17 (27), the stereochemistry of the nucleus cathol (18) being based on the similarities of the coupling constants to those of maytoline (1).
OAc
VH* C Ac? O , ~ : OAc , ; VAc
AcO
H3C' O H
OAc
17
18
Cathidine D
CH3 R' = Ac, Ra = Nic, R3 = Bz, R* = AC or R3 = Ac, R4 = Bz R' = RS = R3 = R4 = H
,
19
CH3
CHa-OAc
A recent note reported that cathidine (as a crude alkaloid fraction) on hydrolysis and then acetylation yielded octaacetyl euonyminol (19) (51). This result conflicts with the formula and structure of purified cathidine D, and this derivative is presumably derived from further alkaloids in C. edulis that have yet to be isolated.
2. Maytine
Maytine (2) (CZ9H,,NO,,) and maytoline (1) were isolated together from Maytenus ovatus, and a comparison of their NMR and IR spectra suggested that they were very similar (1).Both contained a nicotinate and four acetate groups. However, the NMR spectrum of maytine lacked the signal a t 6 3.60 (d, J = 3.5 Hz) assigned to the C-3 proton in maytoline, and the signal for the adjacent C-2 proton (6 5.47) was a multiplet instead of a triplet. Maytine contained a free hydroxyl group ( v , , 3550 cm-l), which was unreactive on attempted acetylation and
226
ROGER M. SMITH
was assumed to be tertiary. As in maytoline, one of the acetate group methyl signals appeared at high field ( 6 l.60), suggesting that acetyl and nicotinoyl groups were in 1,9 relationship. Hydrogenation of maytine with Pd/C gave tetrahydromaytine (20), whose NMR spectrum contained acetyl signals a t 6 2.22, 2.10 (ZMe), and 1.72, the interaction with the heterocyclic ring being lost ( I , 38). Hydrolysis of maytine yielded a C15H2607 polyol, which from its NMR spectrum and the above evidence, was identified as 3-deoxymaytol (21).Maytine thus has the same ester substitution pattern and stereochemistry as maytoline (1).
OAc
CH3
20
OR6
D. ESTERS OF C,,H,,O,
1. Maytoline
POLYOLS
Maytoline (1) (C,9H,,N0,,) was the first alkaloid in this family t o be fully elucidated structuraIly ( I ) . The presence of the weakly basic nicotinate function was first observed by a change in the U v spectrum
227
on acidification. The formula was determined by high resolution mass spectroscopy (HRMS) and elemental analysis, and I R spectroscopy showed the presence of hydroxyl, vmax 3500 cm-l, and ester groups, vmax 1735 cm-l. The nicotinate group gave characteristic mass (m/e 124 and 106),UV, and NMR spectra. The NMR spectrum also contained signals for the partial structure -CHOAcyl-CHOAcyl-CHOH6 5.91 (d, J = 3.5 Hz), 5.60 (t,J = 3.5 Hz), and 3.60 (d, J = 3.5 Hz),a primary C&OAcyl 6 4.96 and 4.40 (ABq J = 13 Hz), and two secondary esters (CHOAcyl) 6 6.16 s, 5.49 (d, J = 7.5 Hz), and a D,O exchangeable proton. Acetylation converted the partial structure to -(CHOAcyl)3and the signal a t 6 3.60 shifted t o 6 4.87 (d, J = 3.5 Hz). On hydrolysis, maytoline gave maytol(22), C15H2608, whose NMR spectrum contained signals for three quaternary methyl groups and no olefinic protons. Maytoline was readily converted to a methiodide, which was examined by X-ray crystallographic analysis (20). The structure and relative configuration were determined but the absolute configuration could not be defined. The results agreed well with the NMR spin-spin couplings.
2. Maytolidine
Maytolidine (23) (C36H41N014) gave UV, NMR, and mass spectroscopy signals assignable to a benzoyl, four acetyl, and a nicotinoyl groups (38). Hydrolysis yielded maytol (22) and acetic and benzoic acids. Benzoylation of 1 gave 3-benzoylmaytoline, which was isomeric with maytolidine but showed a different NMR spectrum, principally in the chemical shifts of the acetyl methyl groups. Detailed examination of the spectrum suggested that the benzoyl group in 23 was a t C-6; C-6H 6 6.23 compared with 6 6.08 in 3-benzoylmaytoline.
IV. Structures of Diesters of Substituted Nicotinic Acids

On hydrolysis, seventeen of the Celastraceae alkaloids (Table IV) yield a pyridine dicarboxylic acid, which in the intact alkaloid is present as a diester at C-3 and (2-12 on the sesquiterpene nucleus. This nucleus is more highly oxygenated than in the alkaloids containing an unsubstituted nicotinate group, and in some cases a (2-8 keto group is present.
A. STRUCTURES OF THE DIACIDS

Three pyridine diacids have been found, each containing a five-carbon side chain at the 2 position of nicotinic acid.
TABLE I V PROPERTIES OF CELASTRACEAE ALKALOIDS CONTAININQ A DIESTER Alkaloid Evonoline (24) Evonine (25) 2-Deacetylevonine (28) Neoevonine (28) Isoevorine 2,B-Didmetylevonine (29) Evozine (27) Isoevonine (47) Alatemine (48) Euonymine (50) Neoeuonymine ( 5 1 ) Euonine (52) Wilforine (54) Wilforzine Wilforgine (55) Wilfordine (53) Wilfortrine (58) Solvent CHCl, unless noted. ECOH. Acetone. Formula C3eH43NOie C3eH&Oi, C.34H41N018
C34H41N018
Mol, wt. (m/e) mp ("C)

~~
[alOa
Sesquiterpene nucleus Formula

~~ ~~
Diaoid Evoninia acid
Reference 32, 34 21 30 23 33 30 33 31, 36, 37 31 26 23 23 31 12,53 15, 53 13, 53 12, 53 13, 53
745 761 7l9 719 719

677
150-158 184-190 135 264-265 185-188 141 288-290 Amorphous 185-193
+ 6.0'
+ 8.4'
+24.9' +22.l0
C34H4iNOie C,,H,,NO,, C32H39N016 C38H43NOl,

C41H46N018
677 761 839 805
+ 13'
30.50b +210
+44'
Evonolinol (4-deoxyevoninol) Evoninol Evoninol Evoninol Evoninol Evoninol Evoninol Evoninol Evoninol Euonyminol Euonyminol Euonyminol Euonyminol Euonyminol Euonyminol Euonyminol Euonyminol
C,,H,,Og
C,,H,4010 Evoninic acid C,,H,40,, Evoninio acid C,,H,40,, Evoninic acid Cl~H24010 Evoninic mid C,,H,,O,, Evoninio acid C,,H,,O,, Evoninio acid C,,H,40,, Wilfordic acid C,,H,40,, C,,H,eOl, C,,H,,O,o C,,H,,Olo C,,H,,O,, C,,H,,O,, C,,H,,O,, Cl,H,,O,, C,,H,,O,, Hydroxywilfordio acid Evoninic acid Evoninic acid Wilfordic mid Wilfordic acid Wilfordic acid Wilfordic acid Hydroxywilfordio w i d Hydroxywilfordio .wid
TI 0
d !
3
m
C,eH4,NOi, C3eH4sNOi7 C3dbNOie

C43H48N018
763
805
867
259-262
C41H47N017
C41H47N019
857 883 873
C43H49N019 C4,H4,N0,,
149-153 169-170 177-178 21 1 175-176 237.6-238
- 20' - 11' - 2.5" + 3OoC
E x
+6OC
+ 25OC + 1ZoC
+ looc
4. 1. Evoninic acid
229
Evoninic acid (4) (C11H13N04; mp 127-133C) was first isolated by Pailer and Libeseller as its optically active dimethyl ester (C13H17N04; [.ID - 42"), from an alkaline hydrolysis of evonine, or in a reduced form as the diol 5 (CllH1,N02), on reduction of evonine with lithium aluminum hydride (LAH) (9).UV spectroscopy suggested that the compounds were pyridine derivatives, and reduction of 5 with HI yielded a compound similar to 2-isobutylpyridine. Oxidation of evoninic acid yielded 2,3-pyridine dicarboxylic acid and a color test on 4 with Fe(I1) showed that the original carboxyl group was not in an a position. The side chain contained two secondary methyl groups (PJMR spectroscopy) and ozonolysis of 4 gave optically active d-2,3-dimethylsuccinic anhydride which defined the structure and stereochemistry as 2S,3X (10). The subsequent X-ray analysis of bromoamtylneovonine confirmed these results (25).Other workers have since reportea more detailed NMR and mass spectra for 4 and its derivatives (33, 50).
2. Wilfordic Acid and Hydroxywilfordic Acid
Wilfordic acid (6) (C,,H,,NO,; mp 195-196C) and hydroxywilfordic acid (7) (CllHl3NO5;mp 178-179OC) were first isolated by Beroza from the alkaloids of Tripterygium wilfordii (12-15). The formulae were determined by analysis, and UV spectroscopy showed that the aromatic carboxyl was not ortho to the basic nitrogen. The hydroxyl group in hydroxywilfordic acid was shown to be adjacent to a carboxyl function by decarboxylation studies (52).On oxidation, both diacids gave acetic, oxalic, and quinolinic acids, showing that a methyl group must be present in the side chain (14).The structures were elucidated by hydrogenation to yield nonane, thus defining the position of the methyl substituent, and by NMR spectroscopy (18). However, their absolute stereochemistry is still undefined, although both compounds are optically active; wilfordic acid, [.ID + 6.98" (H20)and hydroxywilfordic acid, [a],, -24.1" (H,O) (18). Recent work has reported NMR and mass spectra (36)and a detailed mass spectral study of the esters (53). B. ESTERS OF C15H2409 KETOPOLYOL 1. Evonoline During their investigation of the alkaloids of Euonymus eurqaeus, Pailer and his co-workers isolated evonoline (32) (C,,H,,NO,,), which was less polar than the principal alkaloid, evonine. The mass spectrum
230
ROGER M. SMITH
and analysis of evonoline showed that it contains one less oxygen than evonine, and the IR spectrum lacked a band for a hydroxyl group. In the NMR spectrum, the C-4 methyl signal was a doublet 6 1.29 ppm (J = 8 Hz) and thus secondary, unlike the tertiary C-4 (Me) OH group in evonine; the rest of the spectra were very similar (see Table V). From the long range coupling of C-2H and C-4H (J = 1.1 Hz) these protons were assigned to a W diequatorial configuration, and thus the C-4 methyl group was axial, in the same orientation as in evonine. The C-1H and C-9H must both be axial as a strong nuclear Overhauser effect (NOE) (20y0) was demonstrated between them. Evonoline was therefore assigned the structure 24 (32).
OAc
FHZ
AcQ
9R4
24
25 26 27 28 29 80
Evonoline Evonine Neovonine Evozine 2-Deacetylevonine 2,6-Dideacetylevonine Bromoacetylneoevonine
Ac Ac Ac Ac
H H
Ac
H OH OH OH OH OH OH
Ac Ac H
K
Ac H BrAc
Ac Ac AC H Ac AC Ac
An independent report by Budzikiewicz and co-workers (34)reached the same conclusion for the structure of a compound they named 4-deoxyevonine. Their paper illustrated the hWR and mass spectra of 24. Analysis of the mass spectrum suggested that a Maclafferty rearrangement of the C-3 ester group involving a coplanar and hence equatorial C-4H led to a ready loss of COz not found in the mass spectrum of evonine.
231
C. ESTERS OF C,5H,,010 KETOPOLYOL

1. Evonine
Evonine (25) (C3,H4,NO13)was initially isolated as base C by Doebel and Reichstein and reported to be a pentaacetate with the (8). It was reisolated by Pailer and tentative formula C31H39N014 Libiseller as the major component from E . europaeus and named evonine (C36H43-45Nol,) (9). Hydrolysis of evonine yielded formaldehyde, 5 moles of acetic acid, and a diacid Cl1H,,NO4, subsequently elucidated as evoninic acid (4) (10).X-ray analysis of evonine suggested the mol. wt. 764.6 and thus the formula C36H45N017 (mol. wt. 763.73) (54).The formula of polyol nucleus would therefore be C,,H2,010. Studies in Budapest found that if the crude alkaloid mixture from E. europaeus was acetylated, the yield of evonine (semisynthetic) was 70y0 compared to a usual 23y0 (35). On hydrolysis of 25, 7 moles of alkali were consumed to give a polyol that reacted with periodate. The polyol could be converted into a perbenzoate whose IR spectrum still contained a band a t 3500 cm-I from an unacylated tertiary hydroxyl group. A NMR spectrum suggested two C-methyl groups were present in the polyol nucleus, which was thus probably a terpene rather than a sugar (55). Following the report of the structure of maytoline, two groups, Yamada and his co-workers in Japan (21, 22, 24) and Pailer and his co-workers in Austria (32),almost simultaneously but independently published reports of the structure determination of evonine (C36H43NO,,; mass spectrum, m/e 761) based on a polyol nucleus evoninol (31)
(C15H24010).
HoqcH3
HO..
VHaOH
H d O H
~ H ~ O H
51
Evoninol
R = =O R =
32 Euonyminol
< .H OH
<OH
H
33
IsoeuonyminoI
R =
232
ROGER M. SMITH
TABLE OF CELESTRACEAE l H NMR SPECTRA Alkaloid Evonoline (24) Evonine (25) 2-Deacetylevonine (28) Neoevonine (26) 2,6-Dideacetylevonine (29) Evozine (27) Isoevonine (47) Alatamine (48) Euonymine (50) Euonine (52)c Wilfordine (53)
~
c-1
5.79 d (3.4) 5.71 d (3.2) 5.73 d (3) 5.72 d (3.2) 5.67 d (3) 5.87 d (3.4) 5.70 d (3.5) 5.90 d (3.5) 5.55 d (4.0) 5.64 d (3.2) 5.77 d (3.0)
~~
c-2 5.33 ddd (3.4, 2.6, 1.1) 5.29 t (3.2) 4.00 t
c-3 4.84 dd (2.6, 1.2) 4.78 d (3.2) 5.14 d (3) 4.82 d (3.2) 5.24 t (3) 4.80 d (3.0) 4.97 d (3.0) 5.18 d (3.0) 4.72 d (2.5) 4.93 d (3.0) 5.08 d (2.8)
~ ~
c-4 7.13 qdd (8.0, 1.2, 1.1)
C-6 6.45 d (0.9) 6.72 d (1.0) 6.78 bs 5.41 d (1.5) 5.36 d (1) 5.20 s 6.72 d (1.0) 6.82 d (1.0) 7.02 d (1.0) 6.90 s
(3) 5.34 t
(3.2) 3.95 t (3) 5.22 dd (3.4, 3.0) 5.15 t (3.5) 5.46 dd (3.5, 3.0) 5.23 dd (4.0, 2.5) 5.15 dd (3.2, 3.0)
~~~~
Spectra run on solutions in CDCl, unless noted. Chemical shifts are in parts per million relative to TMS. Figures in parentheses are couplings in Hertz. Bands were present as appropriate for ester groups.
a
Subsequent full papers by Yamada and his co-workers have discussed the details of the structure determination (50) and the chemical reactivity (56) of evonine. They found that the NMR spectrum showed the presence of five acetate methyls, two tertiary methyl groups, an aceotoxymethylene (-CH,-OAc), and a hydroxyl group adjacent to a tertiary methyl group (Table V). Decoupling experiments showed the presence of a 1,2,3-triester (-CHOAcyl-),. Reduction of 25 with LAH gave two isomeric C,,H,,O,, polyols, euonyminol (32) and isoeuonyminol (33), implying a keto group was originally present. Analysis of the NMR spectra of their peracetates confirmed this view and led t o the partial structure -CHOH-CO-CHin evonine. Chemical degradation of 25 with NaOMe-NaON gave a pentadeacetyl evonine (mp 257'C), which reacted with 2,2-dimethoxypropane t o give an acetonide. Comparison of the spectra of this compound and 25
V ALEALOIDS CONTAINING A DIESTER~
c-7 3.09 d (0.9) 3.04 d (1.0) C-8 c-9 5.50 s 5.57
8
233
c-126
4.90, 5.34
C-13 1.47 s 1.61 s 1.54 s 1.64 s 1.61 s 1.51 s 1.55 s
C-14 1.29 d (8.0) 1.61 s 1.24 s 1.90 s 1.28 s 1.84 s 1.61 s
C- 15
4.46, 4.80 (12.8) 4.58, 4.82 (13.0) 5.03, 4.60 (11.0) 4.47, 4.92 (13.0) 4.50, 5.18 (13) 4.62 s 4.47, 4.85 (13) 4.85 s 4.50, 5.13 (13.5) 4.43, 5.42 (13.0) 4.21, 4.50 (13.0)
Reference 32 50 30
5.63 s 5.59
8
3.02 d (1.5)
5.51 dd (3.8, 6.2) 5.48 dd (3.0,6.7)
5.69 s 4.49
8
3.22 d (1.2) 3.02 d (1.0) 3.10 d (1.0) 2.33 dd (3.8, 1.0) 2.62 d (3.0) 2.40 dd (1.0, 4.5)
b
C
5.53 s 5.65 s 5.34 d (6.2) 5.20 d (6.7)
(11.3) 3.76, 6.04 (11.7) 3.87, 5.82 (12) 3.78, 6.10 (12.0) 3.76, 6.04 (13) 3.74, 6.09 (11.5) 3.79, 5.81 (12.0) 3.80, 5.94 (12.0) 5.94 d( 1H) (12) 4.10, 5.77 (12.0) 3.77, 5.82 (13.0)
50
30
57
36 26 23 31 26
AB quartet.
Solvent (CD&CO.
showed that evonine contained one primary and four secondary acetate groups and that the triester could be assigned the partial structure -CHOAcyl(CHOAc),-. Acetylation of the acetonide afforded an acetonide triacetate 34, which with aqueous acetic acid was converted to a triacetate. The NMR spectra showed that the primary hydroxyl and the hydroxyl of the a-ketol had been involved in the acetonide formation and must thus be in a 1,3 relationship. Cleavage of the triacetate with Pb(OAc), gave an aldehyde ester triacetate (35). The changes in the coupling constants enabled a second of the secondary alcohols to be related to the ketone in evonine as -CHOH. CO .CH .CHOH-. Potassium tert-butoxide reacted with the aldehyde ester to yield an a$-unsaturated aldehyde ester (36)and formaldehyde. This retroaldol reaction enabled the correlation of most of the partial structures in evonine as 37.The remaining alcohol group,
234
ROGER M. SMITH
YH,OH
Ac?
j
C02CH3
H3C OH
OAc
34
35
C(OH)Me, was related to the triester by the conversion of evonine to a pentamethyl ether by the replacement of acetate by methyl, reduction of the remaining ester functions with LAH to give 38, cleavage of the 3,4-diol to an aldehyde methyl ketone (39), and thus the partial structure 40 could be derived. An important degradation led to the l,%napthoquinone 41, as this related the side chain to the carbon skeleton. Only one oxygen was uncharacterized a t this point, and it was deduced to be ethereal and must be attached to the ring junction and give the tertiary hydroxyl in 41. The structure was then complete except for the orientation of the diacid. Partial methanolysis of evonine gave 42 and complete hydrolysis
CHzOAc
I
AcO&o
AcylO
H
37
'H OAc
36
235
~H,OH
38
~ H ~ O H
39
CHaOAc
H h
Acyl-0 H3C
H
OH
40
OAc
then yielded monomethyl evoninate with the free carboxyl group on the side chain, which therefore must have been attached to C-3. The stereochemistry of the substituents was derived from NMR spectra and by NOE enhancement studies (24). These confirmed that the ring junction was trans and that the C-4 methyl and C-6 protons were diaxial. These conclusions were disputed by KlBsek et al. (57),
OH
I
9 2
OH!
?H
CH,O
OH
AcO
41
42
236
ROGER M. SMITH
although they agreed with the structure from their own unpublished studies, but were reemphasized in the full paper (50) by Yamada. The stereochemistry was conclusively established by the relationship of evonine to neoevonine (6-deacetylevonine) (26) (23) and the X-ray crystallographic analysis of bromoacetylneoevonine (30) (25). During the structural determination, a number of unusual reactions involving the oxygen functions of evonine and neoevonine were noted (56). The independent study by Pailer and his co-workers followed a similar argument to that of the Japanese workers and reached the same conclusion (32).The key compound in their analysis was the unexpected acetal (43) formed by the action of periodic acid on evoninol, which on acetylation gave 44 (c23&&13).This compound contained a ketal and hemiketal (NMR spectra) and led to the elucidation of the tetraol ring system. Further analysis gave the complete structure, the orientation of the diester being derived from the anisotropic effect of the pyridine ring on the C-12 methylene group. Reichsteins group, who were first to work in this area, have subsequently reported the full details of their studies on the isolation and properties of evonine and a number of related alkaloids (33). I n a recent study, a selective recombination of evoninic acid as the
43 44
R = H R = AC
CH,? CO,CO,Et
CH3
OCH,
45
J.
25
46
4.
237
trityl ether 45 and the acetonide 46 yielded a monoester, which after conversion of the trityl group to a methyl ester and then removal of the acetonide, yielded evonine on treatment with sodium hydride (58).
2. Neoevonine, Evozine, Isoevorine, 2-Deacetylevonine, and 2,6-Dide-
acetylevonine These five deacetylevonine alkaloids have all been found as constituents of Euonymus species. The positions of substitution were principally derived by analysis of the NMR spectra (Table V). Originally alkaloid A (8),neoevonine (26) (C,,H,,NO,,) was isolated and the structure reported by the Japanese group (23), and almost simultaneously the full details of its isolation as evorine were reported by Reichstein (33).Acetylation of neoevonine yielded evonine, and the NMR spectrum showed that 26 was 6-deacetylevonine. It was used during the structural and chemical studies on evonine ( 5 0 , 5 6 )and could be prepared from evonine by controlled mild hydrolysis (23, 50). It also could be obtained in high yield by the treatment of evonine with an enzyme preparation from the fruit of E. europaeus (33).On bromoacetylation, 26 yielded a crystalline derivative (30))which was examined by X-ray crystallography (25) to give its relative and absolute configuration. Alkaloid B ( 8 )was reisolated as evozine (27) (C32H3sNO,,) (33),and its structure was determined by NMR spectroscopy as 6,9-dideacetylevonine (57). Hydrolysis of evonine, followed by the acetylation of the pentadeacetyl product, as well as yielding evonine and neoevonine, also gave a second monodeacetylevonine, isoevorine (C,,H,,NO,,), identical with a previously isolated but unpublished alkaloid D (33).However, its NMR spectrum was not reported nor a structure proposed, except that it differed from both 2- and 6-deacetylevonines. and 2,6-dideacetylevonine (29) 2-Deacetyl (28) (C,,H,,NO,,) (C,,H,,NO,,) were isolated from E . europaeus as minor alkaloids and their structures elucidated by NMR spectroscopic comparison with evonine (30).
))
3. Isoevonine
Isoevonine (47) (C,,H,,NO,,) was reported almost simultaneously by groups in Czechoslovakia (36, 37) and in Japan (31, named evonimine). It is isomeric with evonine, but on methanolysis yielded the dimethyl ester of wilfordic acid (6).Similarities between the NMR spectra of the two alkaloids suggested that the rest of the molecules were probably
238
ROGER M. SMITH
identical (Table V). Both contained five acetoxyl groups and could be converted into the hexaacetate of evoninol (31) or by reduction and acetylation into euonyminol octaacetate (19) (31).Selective hydrolysis of the aromatic ester group enabled the orientation of the wilfordic diester to be established (31).
4. Alatamine
Alatamine (48) (C,1H,5N0,,) on mild reduction and acetylation was readily converted t o a mixture of the previously isolated alkaloid wilfordine (53) and its C-7 epimer (26). Thus, alatamine was derived from a C,,H,,O,, keto-polyhydroxy compound, which from its relationship to wilfordine, was linked to benzoic acid, hydroxywilfordic acid, and 4 moles of acetic acid. Acetylation of alatamine and methanolysis yielded a methyl ester, which on comparison with the spectra of the acetate, showed that one of the diacid ester linkages was to C-12. Further acetylation to a hexaacetate, reduction, and cleavage gave 49. This compound could also be prepared from the evonine derivative 42 on acetylation and benzoylation followed by reduction. Thus, both the position of the benzoate and acetate groups, of the second diester linkage, and the presence of evoninol (31) as the nucleus of alatamine were confirmed. The benzoate position also agreed with an NMR study of model C-1, C-2, and C-3 benzoates prepared from evonine.
'
47
48
Isoevonine R' = Ac, RZ = H Alatamine R1 = Bz, Ra = OH
239
'
D. ESTERS OF C15H,,010 POLYOLS
I . Euonymine and Neoeuonymine
Reduction of euonymine (50) (C38H47N018) with LAH yielded the diol5 (from evoninic acid) and euonyminol (32) (23),identical with one of the reduction products of evonine (21). A comparison of the spin couplings of C-9H in euonyminol (32) ( J 8 , g= 6 Hz) and isoeuonyminol (33)( J E S= g 10 Hz) showed that in 50 the C-8 hydroxyl was axial. This assignment was confirmed by an NOE interaction between the diaxial C-6H and C-8H in the octaacetate of isoeuonyminol(33) (24).Methanolysis confirmed the number and position of the acetyl groups in euonymine and that the evoninic acid aromatic carboxyl was attached to C-12 (23). Neoeuonymine (51) (C,,H4,NO1,), isolated with 50, was converted to euonymine on acetylation and, from its NMR spectrum, which lacked the C-6H signal in the 6-7 region (euonymine 6 7.02), was deduced to be 6-deacetyleuonymine (23). The stereochemistry of both compounds was derived from the relationship of euonyminol to evonine (24).
OAc
FHz AcO i OAc

AcO- &,
OAc
50 51
Euonymine R = Ac Neoeuonyrnine R = H
2. Euonine
Euonine (52) (C38H47N018) is isomeric with euonymine and on exhaustive methanolysis and acetylation afforded also euonyminol octaacetate, but dimethyl wilfordate rather than dimethyl evoninate
240
ROGER M. SMITH
(31). Partial methanolysis gave hexadeacetyleuonine methyl ester. Comparison of the NMR spectra enabled the position of the acetyl groups and the orient*ationof the wilfordic acid group to be determined.
AcO
OAc
R
52 Euonine Ac 53 Wilfordine Bz 54 Wilforine Bz 55 Wilforgine Fur 56 Wilfortrine Fur
Ra H OH H (postulated)
H (postulated) OH (postulated)
3. Wilfordine
Initial studies on Tripterygium wilfwdii yielded the crude alkaloid triptergine (C,,H,,NO1 (59),reisolation by Acree and Haller yielded wilfordine, but it was still a mixture (11).Wilfordine (C43H4gN0,g) was finally obtained pure by Beroza (12), who assigned the formula. He showed that it contained 1 mole of benzoic acid, 5 moles of acetic acid, and 2 moles of a non-steam-volatile acid. Further studies (14) identified the nucleus as C15K16(OH)10 and the acid as hydroxywilfordic (7) (14, 18), but no structure was proposed. Subsequently, Yamada et al. isolated wilfordine from Euonymus alatus and related it to the product of the reduction and acetylation of alatamine (48) (26).The stereochemistry of the introduced acetate was whose determined by LAH reduction of wilfordine to euonyminol (32), stereochemistry had already been established (24).Thus, wilfordine (53) must have the same ester substitution pattern as alatamine and an additional axial C-8 acetate instead of a keto group.
4.
241
4. Wilforine and Wilforzine
Wilforine (C,3H,gNOl,) was first isolated by Beroza (22)who showed it to contain one fewer oxygen than wilfordine. Degradation yielded 5 moles of acetic acid, 1 mole of benzoic acid, 1 mole of wilfordic acid, and a " Cl5H1,(OH),, " nucleus (14). Further isolation studies yielded wilforzine (C,,H,,NO,,), whose formula and hydrolysis suggested it was deacetylwilforine (15).It could be converted to wilforine on acetylation (25) and was shown not to be artifact. The C15 nucleus in both wilforzine and wilforine was found to be identical with that from wilfordine by X-ray analysis (14). Despite the recent isolations of wilforine from Maytenus senegalensis (39) and T . wilfordii (53),the full structure has not yet been reported. The biogenetic relationship to wilfordine and the presence of the same nucleus (32) suggest that wilforine differs only in the diacid group and is probably 54. Wilforzine is probably the 6- or 2-deacetyl derivative of 54, by analogy with the derivatives of evonine and euonymine. The name wilforine is noted to be also in use to describe a pregnane from Cynadum wilfordii (39).
5. Wilforgine and Wilfortrine
Wilforgine (C,,H,,NOlg) and wilfortrine (C,,H,,NO,,) were also isolated from T . wilfordii by Beroza (13) and were found to yield 3-furoic acid, 5 moles of acetic acid, and wilfordic or hydroxywilfordic acid, respectively, on hydrolysis. They both contained the same C15 nucleus as wilfordine (14).Although these alkaloids have recently been reisolated (53), their structures have not yet been reported. They probably correspond to those of wilfordine and wilforine in which the benzoate group is replaced by a 3-furoate group (i.e., 55 and 56).
V. Structures of Related Sesquiterpene Esters and Polyols

As well as the sesquiterpene alkaloids that have been found in the Celastraceae, a number of neutral polyester sesquiterpenes have been isolated (Table VI). These compounds are clearly related to the alkaloids and are also based on hydroxylated dihydroagarofurans, in some cases identical with those found in the alkaloids. The ester malkangunin (13) (C24H3207) from Celastrus paniculatus was shown by Wagner and his co-workers to be the acetate benzoate of malkanguniol (14) (CI5H,,O5) (46).Doubt has been cast on the stereochemical assignments by the work of den Hertog and his co-workers,
TABLE VI
NATURALLY OCCURRING POLYESTER SESQUITERPENES FROM CELASTRAOEAE

Ester Ahtolin (61) Euolalin (65) Mctlkangunin (13) Ester A-1 (57) A-2 (58) A-3 (59) Ester B-1 (62) B-4 (63)
Source a
Formula.
Mol. wt. (m/e)
EA EA CP EE EE EE EE EE
756 694 432 756 694 652 674 684
Amorphous 219-221 240-245 95-100 188-192 85-90 112-120 106-110
CP = Celaatrms paniculatwr, EA = Euonymua alatua, E E = E . europaeua. Alternative structure 15 based on polyol 16 (47).
4.
243
who established the different stereochemical structure 1 6 for malkanguniol obtained by the hydrolysis of C. paniculatus seed oil (47) (see Section 111, Al). The position of the benzoate group in 13 was based on the chemical shift of the C-9 proton, 6 6.22, compared with the value of 6 5.3-5.4 in the related Celastrus alkaloids (Table 111). A series of five polyesters has been reported from E m y m u s europaeus but their full structures have not yet been determined (60).ThreeA-1 (57), A-2 (58), and A-3 (59)-are based on the hexaol (60), the remainder-B-1 (62) and B-4 (63)-are based on the isomeric hexaol (64). The substituents and the structures of the hexaols were determined by mass, IH, and 13C NMR spectroscopy, but it was not possible to assign the positions of the ester functions.
OR
CH3
57 58 59 60 61
Ester A-1 R = 3 x Ac, 3 x Bz Ester A-2 R = 4 x Ac, 2 x Bz Ester A-3 R = 3 x Ac, 2 x Bz Alatolin
R = H R = 3 x Ac, 3 x Bz
62
63 64
CH, Ester B-1 R = 2 x Fur, 2 x Ac, 2-methylbutanoyl Ester B-2 R = 2 x Ac, 3 x Fur R = H
244
ROGER M. SMITH
A closely related compound, alatolin (61), also based on the hexaol 60 has been isolated from Euonymus alatus (61). Hydrolysis of 61 yielded 60 (named alatol), whose structure was determined by NMR
studies, including the NOE and by its synthesis from evoninol (32).The NMR spectra of 61 and 57 were measured in different solvents, and insufficient data have been reported to enable a comparison to be made to determine if these two compounds are identical or positional isomers. Euonymus alatus has also yielded euolalin (65) (C,,H4,Ol2), which on hydrolysis gave deoxymaytol (21), 2 moles of benzoic acid, and 2 moles of acetic acid (62).From the mass and NMR spectra, a fifth ester group, a-methylbutyrate, was identified. The substitution pattern was determined by partial hydrolysis and synthetic studies. Studies on further components in Celastrus oils have continued in three laboratories. Work on the hydrolysis products of nonglyceride
OAc
I
-CHaCH,
CH3
65
Euolelin
R'
66 67 68 69
R2 R3
H
CH3 R4 ---OH -OH -OH ---OH
R5
RE
PolyalcoholA OH Polyalcohol B OH Polyalcohol C O H Polyelcohol D O H
OH H OH H OH OH H
-OH OH ---OH H -OH OH H -OH
4 . CELASTRACEAE ALKALOIDS
245
esters in C . paniculatus oils, as well as yielding malkanguniol (16), gave four related polyols, polyalcohol A (66)(C15H2,0,; mp 185-186.5"c), polyalcohol B (67) (C15H2605; mp 236-239"C), polyalcohol C (68) (C,,H,,O,; mp 205-207"C), and polyalcohol D (69)(C15Hzs05; mp 243-245C) (47).Their structures have been determined and related t o malkanguniol by IH and 13C NMR spectroscopy. The hydrolysis also yielded acetic, benzoic, 3-furoic, and nicotinic acids, and thus, these nuclei may represent further Celastrus alkaloids. Polyalcohol B (67) has the same structure and stereochemistry as that reported by Wagner for celapanol (9) (46);however, the coupling in 67 (J8,9 = 10 Hz) ( 4 7 ) differs markedly from the value in the alkaloids 8, 10,and 11 (Js,9 = 7 Hz). Clearly, further studies in this area are needed to clear up the confused stereochemistry. A further group is studying the seed oil of C . orbiculatus and has isolated three esters based on a trio1 (C15H2,04)containing acetic, benzoic, and/or trans-cinnamic acids (63).Detailed structures are under study (64).
VI. Biosynthesis
A systematic 14C-labeling study of t4he Tripterygium wilfordii alkaloids (53) has shown that the pyridine rings of wilfordic acid and hydroxywilfordic acid are derived from nicotinic acid or nicotinamide adenosine dinucleotide (NAD). However, no work has been reported on the origin of the C, side chains of the substituted nicotinic acids. A similar C5 unit is present in the polyesters 62 (60) and 65 (62) as a-methylbutyrate, as the carbon skeleton of 3-furoate in the esters 62 and 63 (go), and in the alkaloids celapanine (S), wilforgine (55), and wilfortrine (56). 3-Furoic acid has been found naturally with a limited distribution, principally in the Celastraceae (65).It was isolated as the free acid from Euonymus autropurpureus (66)and E . europaeus (67) and as an ester in t,he cinnamoyl spermidine alkaloid celafurine from T. wilfordii ( 4 1 ) . The high degree of hydroxylation of the dihydroagarofuran nucleus is unusual in a sesquiterpene and is a characteristic feature of this family. The stereochemistries of the poiyols have some common features. The C-4 methyl group is axial irrespective of a C-4 hydroxyl group. With the exception of polyalcohol D (69) ( 4 7 ) ,the C-1, C-2, C-3, and C-6 hydroxyl groups are, respectively, equatorial, axial, axial, and equatorial. Substitution at C-S and C-9 is highly variable in the nicotinoyl alkaloids (including the polyalcohols) but constant equatorialequatorial in the 0, and Ol0 alcohols.
246
ROGER M. SMITH
W. Biological Properties
Much of the work on this group of alkaloids was prompted by their insecticidal properties. The thunder god vines, Tripterygium wilfordii and l. Forrestii, were both widely used as contact insecticides in rural Chins (68,69).Plants were introduced for testing into the United States (70, 71)and England (72). The American studies led t o the isolation of the alkaloids from T.wilfordii, which were all active against selected 73) but nontoxic to mammals (73). larvae (11, During these studies, insecticidal activity was also found to be Celastrus angulatus (69), present in an unidentified Celastrus species (71), and Euonymus europaeus (72), but so far, the isolated Celastrus alkaloids have not been tested. The isolated alkaloids of Euonymus showed no activity in rats (74)but possessed insecticidal properties (33). The alkaloids of Maytenus owatus were found to be inactive as antitumor agents (38), the activity of the seeds being due to maytansine (40). I n the recent isolation of wilforine from M . senegalesis, it was found to be inactive in antitumor assays (39). E . europaeus (75) and C. paniculatus (28) are both used in folk medicine as cardiototic agents, emetics, and purgatives or as sedatives, but these activities have been related to the presence of cardenolide glycosides rather than to the alkaloids.
Note added in proof. Wagner et al. (76) have recently reported the isolation and structural elucidation of cassinine from Cassine matabelica Loes. (Celastraceae.) The alkaloid is based on a new sesquiterpene nucleus, 4-deoxyeuonyminol, and contains a unique pyridine diacid cassinic acid (3-carboxy y-ethyl-2-pyridinebutanoicacid). Further alkaloids have been reported from Catha edulis (77) and the full details of the structural determination of the polyesters from Eumymus europaeus (78) and Celastrus orbiculatus (79) have been reported.
REFERENCES
1. S. M. Kupchan, R. M. Smith, and R. F. Bryan, J . Am. Chem. SOC. 92, 6667 (1970). 2. D. Gross, Fortschr. Chem. Org. Naturst. 28, 109 (1970). 3. W. A. Ayer and T. E . Habgood, in The Alkaloids (R.H. F. Manske, ed.), Vol. XI, p. 459. Academic Press, New York, 1968. 4. A. D. Krikorian and A. Getahun, Ewn. Bot. 27, 378 (1973). 5. R. A. Heacock and J. E. Forrest, Can. J . Pharm. Sci. 9, 64 (1974). 6. G. B. Marini-Bettblo, Farmaco, E d . S c i . 29, 551 (1974). 7. B. G. Gunde and T. P. Hilditch, J . Chem. SOC. 1980 (1938). 8. I ( . Doebel and T. Reichstein, Helv. Chim. Acta 32, 592 (1949).
4. CELASTRACEAE
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
ALKALOIDS
247
M. Pailer and R. Libiseller, Monatsh. 93, 403 (1962). M. Pailer and R. Libiseller, Monatsh. 93, 511 (1962). F. Acree, Jr. and H. L. Haller, J. A m . Chem. SOC. 72, 1608 (1950). M. Beroza, J. Am. Chem. Soc. 73, 3656 (1951). M. Beroza, J. Am. Chem. SOC. 74, 1585 (1952). M. Beroza, J. Am. Chem.SOC. 75, 44 (1953). M. Beroza, J. Am. Chem. Soc. 75, 2136 (1953). M. Beroza, A d . Chem. 22, 1507 (1950). H. Briiuniger, Pharmazk 11, 115 (1956). M. Beroza, J. Org. Chem. 28, 3562 (1963). M. Cais, D. Ginsburg, and A. Mandelbaum, I U P A C Symp. Chem. Nat. Prod., 31tE 1964 Abstracts, p. 95 (1964). 20. R. F. Bryan and R. M. Smith, J. Chem. SOC. B 2159 (1971). 21. H. Wada, Y. Shizuri, K. Yamada, and Y. Hirata, Tet. Lett. 2655 (1971). 22. Y. Shizuri, H. Wada, K. Sugiura, K. Yamada, and Y. Hirata, Tet. Lett. 2659 (1971). 23. K. Sugiura, Y. Shizuri, H. Wada, K. Yamada, and Y. Hirata, Tet. Lett. 2733 (1971). 24. H. Wada, Y. Shizuri, K. Sugiura, K. Yamada, and Y. Hirata, Tet. Lett. 3131 (1971). Perkin Trans. 2 1268 (1972). 25. K. Sasaki and Y. Hirata, J . Chem. SOC., 26. Y. Shizuri, K. Yamada, and Y . Hirata, Tet. Lett. 741 (1973). 27. M. Cais, D. Ginsburg, A. Mandelbaum, and R. M. Smith, Tetrahedron 31,2727 (1975). 28. E. Heckel, Doctoral Thesis, University of Munich, 1974. Tet. Lett. 213 (1974). 29. H. Wagner, E. Heckel, and J. @onnenbichler, 30. L. Crombie, P. J. Ham, and D. A. Whiting, Phytochemktry 12, 703 (1973). 31. K. Sugiura, K. Yamada, and Y. Hirata, Tet. Lett. 113 (1973). 32. M. Pailer, W. Streicher, and J. Leitch, Monatsh. 102, 1873 (1971). 33. A. Klhsek, F. santavjr, A. M. Duflleld, and T. Reichstein, Helv. Chim. Acta 54, 2144 (1971). 34. H. Budzikiewicz, A. Romer, and K. Taraz, 2.Naturforsch., Ted B 27, 800 (1972). 35. 0. Clauder, K. Bojthe-HorvBth, and I. Hutbs, Herba Hung. 8, 41 (1969); Cd 72, 103666 (1970). 36. L. DlibravkovB, L. Dolejs, and J. Tomko, Collect. Czech. Chem. Commun. 28, 2132 (1973). 37. L. DlibravkovB, J. Tomko, and L. DolejS, Phytochemktry 12, 944 (1973). 38. S. M. Kupchan and R. M. Smith, J. Org. Chem. 42, 115 (1977). 39. M. Tin-Wa, N. R. Farnsworth, H. H. S. Fong, R. N. Blomster, J. Trojbnek, D. J. Abraham, G. J. Persinos, and 0. B. Dokosi, Lluydia 34,79 (1971); N. R. Farnsworth, J. Phurm. Sci. 62, 1028 (1973). 40. S. M. Kupchan, Y. Komoda, W. A. Court, G. J. Thomas, R. M. Smith, A. Karim, C. J. Gilmore, R. C. Haltiwanger, and R. F. Bryan, J. Am. Chem. SOC. 94,1354 (1972). 41. S. M. Kupchan, H. P. J. Hintz, R. M. Smith, A. Karim, M. W. Cass, W. A. Court, and M. Yatagai, J. Chem. SOC., Chem. Cornmun. 329 (1974). 42. G. Englert, K. Klinga, Raymond-Hamet, E. Schlittler, and W. Vetter, Helv. Chim. Acta 56, 474 (1973). 43. S. M. Kupchan, Y. Komoda, G. J. Thomas, and H. P. J. Hintz, J. Chem. SOC., Chem. Commun. 1065 (1972). 44. D. W. Bishay and Z. Kowalewski, Herbu Pol. 17, 97 (1973); 17; 233 (1973); D. W. Bishay, Z. Kowalewski, and J. D. Phillipson, J. P h r m . Pharmcol. 23, 2445 (1971); 24, 169P (1972); Phytochemktry 12, 693 (1973). 45. M. S. Karawya, M. A. Elkiey, and M. G. Ghourab, J. Pharm. Sci. U.A.R. 9, 147 (1968); M. A. Elkiey, M. S. Karawya, and M. G. Ghourab, &id. 159; G. Rucker, H. Kroger, M. Schikarski, and S. &6dan, Plan& Med. 24, 61 (1973).
248
ROGER M. SMITH
46. H. Wagner, E. Heckel, and J. Sonnenbichler, Tetrahedron 31, 1949 (1975). 47. H. J. den Hertog, Jr., C. Kruk, D. D. Nanavati, and S. Dev, Tet. Lett. 2219 (1974); D. D. Nanavati, J. Oil Tech. Ass. Indiu 7 , 51 (1975). 48. H. J. den Hertog, Jr., J. T. Hackmann, D. D. Nanavati, and S. Dev, Tet. Lett. 845 (1973). 49. A. B. van Egmond, S. Harkema, and T. C. Van Soest, in preparation. 50. Y. Shizuri, H. Wada, K. Sugiura, K. Yamada, and Y. Hirata, Tetrahedron 29, 1773 (1973). 51. H. Luftmann and G. Spiteller, Tetrahedron 30, 2577 (1974). 52. M. Beroza, Anal. Chem. 25, 177 (1953). 53. H. J. Lee and G. R. Waller, PhytochemGtry 11, 2233 (1972); H. J. Lee, Ph.D. Thesis, Oklahoma State University, Stillwater, 1971; Dw8. Abstr. B 564 (1972). 54. R. Libiseller and A. Preisinger, Momztsh. 93,417 (1962). 55. 0. Clauder, I. Huths, and K. Bojthe-Horvhth, Symp. Biochem. Physwl. Alkaloide 203 (1969); CA 77, 140360 (1972). 56. Y. Shizuri, H. Wada, K. Yamada, and Y. Hirata, Tetrahedron 29, 1795 (1973). 57. A. Klhsek, Z. Samek, and F. santavf, Tet. Lett. 941 (1972). 58. K. Sugiura, K. Yamada, and Y. Hirata, Chem. Lett. 579 (1975). , 3 (1937); S. Hwang, 59. M. Chou, S. Hwang, and Y. Hsu, Chdah Agric. Quart. 1 Kwangsi, Agric. Ex. Stn. Bull. No. 5 (1939). 60. H. Budzikiewicz and A. Romer, Tetrahedron 31, 1761, 2638 (1975). 61. K. Sugiura, Y. Shizuri, K. Yamada, and Y. Hirata, Tet. Lett. 2307 (1975). 62. K. Sugiura, Y. Shizuri, K. Yamada, and Y. Hirata, Chem. Lett. 471 (1975). 63. R. W. Miller, C. R. Smith, Jr., D. Weisleder, R. Kleiman, and W. K. Rohwedder, fipid8 9, 928 (1974). 64. C. R. Smith, personal communication. 65. W. Karrer, Konstitution und Verkommen der organischen Pflanzenstoffe. Birkhauser, Basel, 1958. 66. H. Rogenson, J . Chem. Soc. 101, 1040 (1912). 67. E. Ramstad, J . Am. Pharm. A880C. 42, 119 (1953). 68. T-H. Cheng, J. Econ. Entoml. 38, 491 (1945). 69. S-F. Chiu, J. Sci. Food Agric. 1, 276 (1950). 70. W. T. Swingle, H. L. Haller, E. H. Siegler, and M. C. Swingle, Science 93,60 (1941). 71. C. S. Lee and R. Hansberry, J . Econ. Entoml. 36, 915 (1943). 72. F. Tattersfield, C. Potter, K. A. Lord, E. M. Gillham, M. J. Way, and R. I. Stoker, Kew Bull. 3, 329 (1948). 73. M. Beroza and G. T. Bottger, J. Econ. Entoml. 47, 188 (1954). and F. gantavf, Acta Univ. Palackri. Olomuc. 11, 29 74. 0. Tlilupilovh-Krestj.nov& (1956). 75. A. Meyrat and T. Reichstein, Pharm. Acta Helv. 23, 135 (1948). 76. H. Wagner, R. Briining, H. Lotter, and A. Jones, Tet. Lett. 125 (1977). Chem. 77. R. L. Baxter, L. Crombie, D. J. Simmonds, and D. A. Whiting, J. Chem. SOC., Commun. 463, 465 (1976). 78. A. Romer, H. Thomas, and H. Budzikiewicz, 2. Naturforsch., Teil 31 B, 607 (1976). 79. c. R. Smith, Jr., R. W. Miller, D. Weisleder, W. K. Rohwedder, N. Eickman, and J. Clardy, J . Org. Chem. 41, 3264 (1976).
THE BISBENZYLISOQUINOLINE ALKALODSOCCURRENCE. STRUCTURE. AND PHARMACOLOGY

M. P. CAVA. K . T. BUCK.
University of Penmylvania Philadelphia. Penmylvania
and K . L . STUART
University of the West Indies Kingston. Jamaica
I Introduction ...................................................... I1. Structure Revisions ................................................ A Chondrocurine ................................................. B Chondrofoline .................................................. C. Fetidine ....................................................... D. Micranthine.................................................... E Thalfoetidine .................................................. F. Tubocurarine Chloride .......................................... 1 1 1 . New Alkaloids..................................................... A . Belarine ....................................................... B . Bisjatrorrhizine Chloride ........................................ C. N, N-Bisnoraromoline ........................................... D . Cancentrine.................................................... E Cepharanoline.................................................. F Chelidimerine .................................................. G Cocsuline ( = Effirine, Trigilletine) ................................ H Cycle~urine ................................................... I Cycleadrine .................................................... J Cycleahomine Chloride .......................................... K Cycleanorine................................................... L Cycleapeltine .................................................. M Dauricinoline .................................................. N . Dauricoline .................................................... 0. 0-Desmethyladiantifoline........................................ P. N'-Desmethyldauricine .......................................... Q 12'.O.Desmethyltrilobine ........................................ R . 0, N.Dimethy1micranthine ....................................... S. (-))-Epistephanine .............................................. T Espinidine..................................................... U Espinine ...................................................... V . Funiferine .....................................................
. .
. . . . . . . . . .
. .
250 251 251 252 252 253 255 255 257 257 258 258 260 261 261 262 263 264 265 266 267 267 268 269 270 270 271 272 272 273 274
250
M P . CAVA. K . T . BUCK. AND K . L STUART
W.Isotenuipine ................................................... X 0-Methyldauricine .............................................. Y . 0-Methylmicranthine ........................................... Z . Nemuarine .................................................... AA . 2.N.Norberbamine ............................................ B B. 2-N-Norobamegine ............................................ CC. Nortiliacorine.A, Nortiliacorinine.A, and Nortiliacorinine-B ........ DD. Oxoepistephanine ............................................. EE . Pakistanamine ............................................... FF Pakistanine .................................................. GG Penduline .................................................... HH. Stepinonine .................................................. I1 Telobine ..................................................... JJ Thalfhe ..................................................... K K . Thalfinine .................................................... LL. Thalictrogamine .............................................. MM Thalictropine ................................................. NN . Thalidoxine .................................................. 00 Thalisopidine ................................................. PP Thalmelatidine ............................................... QQ . Thalmineline ................................................. RR Thalrugosamine .............................................. SS Thalrugosidine ............................................... TT. Thalrugosine (E Thaligine) .................................... UU . Toxicoferine .................................................. W Tricordatine.................................................. IV . Known Alkaloids from New Sources.................................. V. Methodsand Techniques ........................................... A Spectrometry .................................................. B Chemical Methods .............................................. VI. Pharmacology ..................................................... VII . Bisbenzylisoquinoline Alkaloids Tabulated by Molecular Weight ......... VIII. Appendix ......................................................... References ........................................................
. . . .
. . . . . .
. .
275 275 276 276 277 278 278 279 280 281 282 283 285 286 287 287 288 289 289 290 291 292 293 294 295 296 297 297 297 298 300 301 304 312
I Introduction
It is the purpose of this chapter to review the recent chemistry of the bisbenzylisoquinoline alkaloids . The previous review in this treatise covered the literature up to the beginning of 1970. With the exception of a few 1969 references. which were inadvertently omitted from the previous review (Volume XI11 of this treatise). we have covered the period 1970-1973. the 1973 coverage being defined as inclusive of the last issue of Chemical Abstracts for that year. and an appendix similarly covers the 1974 period . All aspects of bisbenzylisoquinoline research have been included. with the exception of synthesis. which is the subject of Chapter 6 in this volume .
5.
BISBENZYLISOQUINOLINE ALKALOIDS
251
We have defined a bisbenzylisoquinoline alkaloid in the broadest sense, so as to cover compounds in which one (e.g., fetidine) or even both (e.g., cancentrine) of the monomeric benzylisoquinoline units may be biogenetically modified. We have included a table (see Section VII) of all bisbenzylisoquinoline alkaloids arranged in increasing order of molecular weight. We feel that this table should be of considerable practical utility to workers in this area who wish to determine rapidly if a compound they have isolated and examined only mass spectrometrically may be identical with one of these alkaloids. The authors have also introduced a brief section describing new and useful techniques, both chemical and spectroscopic, dealing with methods of structure elucidation of bisbenzylisoquinoline alkaloids. The section on pharmacology is not intended to be an exhaustive coverage but should serve as a guide to current general aspects of this area for these alkaloids during the period under review.
I I .
Structure Revisions
A. CHONDROCIJRINE
The sodium thiophenoxide N-demethylation of (R,R)-( + )-tubocurarine chloride (new structure 1) has been reported as giving the presumably new base (+)-tubocurine ( 1 ) . Direct comparison of the latter with ( + )-chondrocurine has now shown these to be identical (2). The former structure 2 for chondrocurine must therefore be discarded in favor of structure 3. The bismethochloride of 3 is (+)-chondrocurarine chloride, ( 4 ) ; the latter structure has recently been confirmed by an X-ray crystallographic analysis (3).
1 R = H 4 R=Me
R1 = H , R , = Me R, = Me,R, = H
252
M. P. CAVA, K.
T. BUCK,
A N D K. L. STUART
B. CHONDROFOLINE
Chondrofoline was originally shown by King to have the same skeleton as curine, and the alternative structures 5 and 6 were proposed for it ( 4 ) . The new structure 7 has recently been assigned to chondrofoline on the basis of a comparative NMR and mass spectral study of chondrofoline, its 0-trideuteriomethyl derivative, and related known alkaloid derivatives of established stereochemistry ( 5 ) .
Me0
OH
5 6
R, = Me,R, = H R, = H , R , = Me
C. FETIDINE
On the basis of earlier reported chemical degradation, fetidine was assigned structure 8 ( 6 ) . Subsequently, mass spectral data in general support of this structure have been reported (7). More recently, a 220 MHz NMR study of fetidine revealed the presence of an AB quartet (J = 8.5 Hz) centered a t 6 6.75 (1H) and 6 6.81 (lH), indicating the
MH
3
'.=
Me0
/
OMe
OMe
0
8
5 . BISBENZYLISOQUINOLTNE ALKALOIDS
253
MH e
Me0
presence of an adjacent pair of aromatic hydrogens. This fact, in conjunction with earlier evidence, requires a revision of the structure of fetidine from 8 to 9 (8).
D . MICRANTHINE
I n 1953, structure 10 was proposed for micranthine (9). Reinvestiga(M+ 548)] by NMR tion of this alkaloid [mp 193-195C; C34H32N205
OH
10 R, = H, Ra = Me or vice verm R, = H, R, = Me or vice versa
indicated the presence of one methoxyl and one AT-methylgroup, and of key significance, ten aromatic protons, thus invalidating structure 10. The trilobine-type structure (11) has now been proposed for micran11). thine (10, The mass and IR spectra of 0,N-dimethylmicranthine (12) (mp 210-214C) and isotrilobine were very similar, and the NMR spectra
254
M. P. CAVA, K. T. BUCK, AND K . L. STUART
0% 11 R1 = R, = H a = Me 12 R1 = R 13 R1 = CD,, R, = Me
were superimposable, but the specific rotations of these compounds were opposite in sign. Both 12 and isotrilobine yielded the same Hofmann degradation product. Since the structure of isotrilobine has been confirmed by synthesis (12)and its stereochemistry is known from degradation to be S,S (13),it follows that micranthine must be R,R, as shown in structure 11. The position of the phenolic hydroxyl, previously established by ethylation and degradation, was confirmed by mass spectrometry. The location of the secondary and tertiary amine functions was determined by the following experiments. Oxidative photolysis of 12 yielded the dialdehyde 14 and a lactam carbinolamine, which was reduced with NBH to the aminolactam 15. When O-methyl-N-triCHO
OMe
I
Me
14
15 16
R =Me R = CD,
deuteriomethylmicranthine (13,50%deuterium incorporation, prepared by alkylating 0-methylmicranthine with formaldehyde-d, and NBD) was similarly degraded, the product was shown by NMR to be 16, thus establishing the secondary nitrogen at position 2' of 11.
5 . BISBENZYLISOQUINOLINE ALKALOIDS
255
E. THALFOETIDINE
Thalfoetidine was previously assigned structure 17 (14). Its earlier chemistry supports the structural features of 17 apart from the location of the ether termini of the isoquinoline units. Direct comparison has now shown that 0-methylthalfoetidine is identical with thalidasine (18). Thalfoetidine must therefore be assigned structure 19 (15, 16). I n further support of structure 19, the racemic form of the thalfoetidine degradahion product 20 has been synthesized and the spectral identity of its diethyl ether with naturally derived material has been established (17).
OMe
I
?H
"H
"H
OH
17
20
18 19
R = Me R = H
F. TUBOCURARINE CHLORIDE
The long-accepted bisquaternary structure 4 for ( + )-tubocurarine chloride has been shown to be incorrect; the alkaloid is actually the related monoquaternary salt 1 (2). The NMR of 1 shows only three N-methyls, one of which shifts upfield on basification, showing it to be a tertiary N-methyl. Benzylation of tubocurarine did not give an 0dibenzyl derivative as required by the old structure 4, but rather an
256
M. P. CAVA, K . T. BUCK, AND K . L. STUART
O-dibenzyl-N-benzyl derivative. Similarly, three methyls were introduced on complete methylation, the product being identical with ( + )-chondrocurine dimethiodide (21). The tertiary and quaternary nitrogens of 1 were distinguished by the sodium-ammonia cleavage of 0,O-dimethyltubocurarine acetate (22) (from 1 acetate and diazomethane). The nonphenolic, optically inactive Emde product 23, was obtained in addition to (8)-N-methylcoclaurine (24), identified as its 0,O-dimethyl ether methiodide.
M e 2 N b : M e
22
1 R = H R = Me (as metate)
Me0 M e 0p
21-
0>
'M N H
e 2
OMe
Me0
23 24
The new structure 1 for tubocurarine chloride has been confirmed by an X-ray crystallographic analysis (18,19).I n the crystal, the molecule assumes a folded conformation with the phenol ring protruding from the center of the molecule; the N-N distance is 8.97 8.
5.
257
A variable temperature NMR study of 1 has revealed interesting aspects of its solution conformation (20). The very highly shielded C,. proton a t 6 4.80 moves slightly downfield to 6 5.08 a t 125OC as the disubstituted central benzene ring begins to rotate. Indeed, the protons of the latter ring (at Cl0,, Cllr, C1,,, and C,,,) are nonequivalent a t room temperature but begin to coalesce to an AA'BB' pattern as rotation increases at elevated temperatures. The trisubstituted central ring is frozen even a t 125OC, and the protons a t Cl0, C13, and C,, are unaffected by temperature changes.
III. New Alkaloids

A. BELAXIXE Belarine (25) [C,,H,,N,O,; mp 158-160C; [aID - 222" (CHCI,)] has been isolated from the root bark of Berberis laurina Billb. (21).Methylation of belarine yielded the previously isolated alkaloid O-methyl-
H'
25 26
R = H R = Me
isothalicberine (26). Structural proof of belarine therefore also firmly establishes the structure of isothalicberine. 0-Ethylation of belarine followed by sodium-ammonia cleavage yielded the tetrahydroisoquinolines 27 and 28, the latter being identified as the diethyl derivative
29.
When belarine was treated with D,O under basic conditions no proton exchange was noted; this fact provides evidence in support of an ether bridge at C, rather than a t C,, since a hydrogen ortho to a phenolic group (C,) should have exchanged. Further support for the absence of a C,-linked ether bridge was obtained by an acid-catalyzed exchange experiment on 25 in D,O; when the product was ethylated and subjected t o sodium-ammonia cleavage, compound 27 was obtained in which deuterium was shown to be located at C, by NMR and mass spectrometry.
258
M. P.
C A V A , K.
T. BUCK, AND K . L. STUART
R, = Me,R1 = E t R, = H,Ra = Me R, = Et,R , = Me 30 R, = RP = Me

27 28 29
Reduction of methyl ether 26 with sodium in trideuterioammonia afforded compound 30 with deuterium a t C, and Cll, thus establishing the points of attachment of the diphenyl ether links to rings B and E (22). B. BISJATRORRHIZINE CHLORIDE Bisjatrorrhizine chloride (31)C40H38N208C12; dihydrate darkening > 270C) was isolated from the roots of Jatrorrhiza palmata Miers (23). The orange-yellow 31 has a UV-visible spectrum characteristic of a berbine alkaloid, and it gives a deep red coloration with base, reminMethylation of 31 with iscent of the phenolic berbine jatrorrhizine (32). methyl sulfate and alkali gave both a monomethyl derivative (33) and a dimethyl derivative (34), showing the presence of two phenolic groups. Neither phenolic group is ortho or para to an aromatic hydrogen, since no deuteration occurred when 31 was heated with DCl. Borohydride reduction of 31 afforded two diastereomeric tetrahydro derivatives (35). A comparison of the NMR spectrum of 31 with those of other known berbine salts, as well as an analysis of the mass spectra of the tetrahydro bases (35), led to the proposed structure 31 for the original alkaloid. Confirmation of this structure was obtained by its synthesis from jatrorrhizine chloride (32) by oxygenation in the presence of platinum. Bisjatrorrhizine chloride is the first example of a bisberbine alkaloid. C. N,N-BISNORAROMOLINE N,N-Bisnoraromoline (36) [C,,H,,N,O,; mp 206C (acetone); + 177" ( 1 N HCI)] was isolated from Pycnarrhena ozuntha Diels ( 2 4 ) . Formaldehyde-sodium borohydride methylation afforded aromoline (37), and further treatment of this derivative with diazomethane
5.
259
HO
M e O %
'
32
I
OM0 OM0
2c1-
OMe
31 Rl = R, = H 33 R, = H, R, = Me 34 Rl = Ra = Me
H N * o , MeO'
'
36 Rl = Ra = H 37 Rl = Me, Ra = H 38 Rl = Ra = Me
260
gave obaberine (38). Since the absolute configuration of aromoline is known from sodium-ammonia cleavage studies (25, 26), N,N-bisnoraromoline is therefore unambiguously established as 36. It is apparently the first reported bisbenzylisoquinoline alkaloid containing two secondary nitrogens, perhaps because of the low solubility in common organic solvents observed for 36 and expected for similar alkaloids.
D. CANCENTRINE
Cancentrine (39) (C,,H,,N,O,, mp 238C) occurs in Dicentra
canadensis Walp (27). It was, in fact, first isolated and characterized
over forty years ago as FZ2, an alkaloid of unknown structure (28, 29). The IR spectrum of cancentrine reveals the presence of both hydroxyl and carbonyl bands. Its NMR shows t,he presence of three aromatic methoxyls and one N-methyl group. The second nitrogen of 39 is essentially nonbasic. The phenolic group of 39 can be methylated, affording 0-methylcancentrine (40), and acetylated to give O-acetylcancentrine (41). Conversion of 39 to its methiodide, followed by a Hofmann degradation, gave the methine base 42. Hydrogenation of 42 followed by treatment with diazomethane afforded the 0-methyl dihydromethine base 43. The structure of 43 was revealed by an X-ray crystallographic determination of its hydrobromide. Spectral studies (UV and NMR) showed that only the expected single chemical changes
\ I
42
OM0
39 40
41
OM0
43
R = H R =Me
R = Ac
5.
261
had occurred in the conversion of 39 to 43.The terminus of the original bridge of 39 was assigned by an NMR comparison of 39 with codeine. The position of the phenolic hydroxyl of 39 was deduced by noting that in going from 39 to its 0-acetate 41 an aromatic proton moves downfield from 6 7.51 to 6 7.88, behavior indicative of the presence of an aromatic hydrogen para to the hydroxyl. This assignment was confirmed by nuclear Overhauser studies, which showed that each methoxyl of 39 is ortho to an aromatic proton. Cancentrine is the first member of a novel class of bisbenzylisoquinolines derived from one morphine-like and one cularine-type unit.
E. CEPHARANOLINE
The root tubers of Stephania cepharantha Hayata have yielded cepharanoline (44)[C,,H,,N,O,; mp 270C (dec.);[a]F + 319' (CHCl,)] (30). Treatment of cepharanoline with diazomethane produced the known alkaloid cepharanthine (45). The location of the phenolic group a t Clz. was stated to be based on mass spectral evidence.
44
45
R = H R =Me
F. CHELIDIMERINE
Chelidimerine (46) [C43H,,N,09, (M+ 720); mp 258-260C; [a]i4 f 01 has been recently isolated from Chelidonium majus L. (31). This novel alkaloid has been synthesized by base-catalyzed condensation of sanguinarine (47) and acetone dicarboxylic acid, a method previously used for the preparation of bis(1 1-hydrochelerythrine)acetone (48), also a known alkaloid (32).
262
M. P. C A V A , K . T. BUCK, AND K . L. STUART
OH -
% 1 R
46 48
'i
41
RlR2 = OCH,O
R1 = R, = OMe
G. COCSULINE (33) [ = EFFIRINE (34),TRIGILLETINE (35)]

Cocsuline (49) (C35H34N205; mp 272-2'74C; [aID+ 280") was first isolated from the leaves and stems of Cocculus pendulus Diels (33). Cocsulineyielded a picrate (mp 194-196"C), O-methylcocsuline (mp 212214"C, [I.D + 289"), and O-ethylcocsuline. Recently, cocsuline has also been reported from Triclisia gillettii (DeWild) Staner (34, 35) and T . subcordata Oliv. (35)under the names effirine (34)and trigilletine (35) [mp 272-274C; [a]g2+ 348.2' (pyridine); acet,ate, mp 166-168"C] (35). O-MethyIcocsuIinewas shown to be identical with the known alkaloid isotrilobine (50). The location of the free hydroxyl group of 49 at position 12' rather than at 6 was established by mass spectral comparison
OMe
0
49 R = H 50 R = M e
12'
OR
5. BISBENZYLISOQUINOLINE ALKALIODS
263
of the alkaloid, its ethyl ether and acetate. I n all cases, intense peaks were observed at mle 350 and m/2e 175 (loss of the top portion of the molecule at a).
H. CYCLEACTJRINE
Cycleacurine (51) [C35H3,N20S. 2H,O; - 202 (MeOH)] was isolated from Cyclea pe2tatu Hook. f. et Thorns. (36); purification was effected by way of the bishydrobromide (mp 293-296C). Its bathochromic UV shift in base revealed its phenolic nature. Diazomethane
+
OR
264
M. P.
C A V A , K.
T. BUCK, AND X. L. STUART
alkylation of cycleacurine afforded the 0-trimethyl derivative (52), which was identical with 0-dimethyl-(S)-curine(53) (37), except for the opposite sign of its rotation; 52 is consequently the optical antipode of 53. The positions of the phenolic functions of cycleacurine were deducible from a study of the sodium-ammonia cleavage of O-triethylcycleacurine (54). The structure of the diphenolic cleavage product (55) was apparent, since it contained an ethoxyl group. The nonphenolic product was assigned structure 56 from spectral considerations. I t s mass spectrum gave an isoquinoline fragment at m/e 220 showing that one of the two ethoxyls must be an isoquinoline substituent. The methoxyl of 56 appears in its NMR a t 6 3.84, indicative of a C, methoxyl rather than a more shielded C, methoxyl.
I. CYCLEADRINE
Cycleadrine (57) (C,,H,,N,OG; mp 160-162"C) is an optically inactive base found in the roots of Cyclea peltata (36).Alkali caused a bathochromic shift in its UV spectrum, indicating its phenolic nature. Reaction of cycleadrine with diazomethane afforded an 0-methyl derivative 58, which was identical with isotetrandrine (59), except for its lack of optical activity. The mass spectrum of cycleadrine showed a strong peak at m/e 381 for the linked isoquinoline units revealing that
M e O m
57 R = H 58 R = Me ( R S
+ 5R racemate)
MeN H'
M
-*
5.9
5.
265
one of these must contain the phenolic hydroxyl group. It is known that only the right hand isoquinoline unit of a C,-C,, head-to-head base is lost singly (38);the peak at mle 417 (M-191) indicates that this unit in cycleadrine must bear a methoxyl at C6,and that the hydroxyl must be born on the left-hand head unit. Finally, the hydroxyl must be a t C, rather than a t C,, since a C, methoxyl in related compounds is highly shielded ( 8 3.20), whereas the highest field methoxyl of cycleadrine appears a t 6 3.73.
N
J. CYCLEAHOMME CHLORIDE
+ 103" (CHCl,)] was isolated from Cyclea peltata roots (36). Its NMR
showed one tertiary N-methyl a t 6 2.37 and two quaternary N-methyls at 6 3.54 and 6 3.30. Cycleahomine was shown to be a monoquaternized tetrandrine, since reaction of 60 with methyl iodide gave tetrandrine bismethiodide (61). On the other hand, reaction of tetrandrine with one equivalent of methyl iodide affords not cycleahomine iodide, but the
Cycleahornine chloride (60) [C,,H,,N,O,C1;
mp 190-194"C,
[.ID
C1- Me,N+
H '
, OMe '
60
61
isomer 62. Since the demethylative carbamylation of tetrandrine is known to occur selectively a t the right-hand isoquinoline unit (see cycleanorine), the selective N-methylation giving 62 must occur a t the same site. Cycleahomine is therefore the isomer of 62, namely 60.
266
M. P.
C A V A , K . T. BUCK, AND
K. L. STUART
62
K. CYCLEANORINE
Cycleanorine (63) [C,,H,,N,O,; mp 171-172C; [aID + 308" (CHCl,)] was isolated from CycZeapeZtataroots (36).Its NMR showed the presence of only one N-methyl (at 6 2.33). N-Methylation of cycleanorine by formaldehyde and sodium borohydride (39) gave tetrandrine (64). The position of the secondary nitrogen of cycleanorine was revealed by its mass spectrum, which showed a peak at m/e 431 (M-177),characteristic of the loss of the right-hand isoquinoline unit of a C,-C7, dimeric alkaloid. Finally, cycleanorine was prepared from tetrandrine (64) by selective N-demethylation using the carbamate method (40). Thus, reaction of 64 with methylchloroformate gave the monocarbamate 65, alkaline hydrolysis of which afforded 63.
63
64 65
R =Me R = COOMe
5.
BISB ENZYLISOQUINOLINE ALKALOIDS
267
L. CYCLEAPELTINE
Cycleapeltine (66) [C3&40X206; mp 232-234OC; [aID - 106" (CHCI,)] was isolated from the roots of Cyclea peltata (36).The NMR and mass spectral data for cycleapeltine were in accord with those reported for limacusine (67), except that the optical rotation w-as of opposite sign. Cycleapeltine should therefore be the optical antipode (66)of limacusine. I n accord wit,h this proposal, reaction of (66) with diazomethane gave an O-methyl derivative that was identical with the known O-methylrepandine (68).
MeN
H '
wo
66 68
: : q N M e
"H
R = H R = Me
M. DAURICINOLINE
Dauricinoline (69) [C,,H4,N206; pale yellow powder; [a]$1 - 94.6" (MeOH)] was isolated from Menispermum dauricum DC. (41). NMR evidence was given to support the presence of two N-methyl, three methoxyl, and two hydroxyl groups. Treatment with diazomethane yielded O-methyldauricine, thus establishing dauricinoline as the O-methyl derivative (70) of the alkaloid dauricoline (71), also isolated from Menispermum dauricum (42).I n further confirmation of structure 69, sodium-ammonia cleavage of the 0,O-diethyl derivative 72 afforded (R)-( - ) - 1 -(p-ethoxybenzyl)-6-ethoxy-7-methoxy-2-methyl-1,2,3,4tetrahydroisoquinoline (29) and (R)-( - )-armepavine (73).
268
M. P. CAVA, K.
T. BUCK,
AND K. L. STUART
OM0
Me0
69 70 71 72
R, = H, Ra = Me R, = R, = Me R, = R, = H R, = Et, R, = Me
MeO' " q
'
N
&
fH . e
73 R, = Me, R, = H 29 R, = R, = Et
N. DAURICOLINE
Menispermum dauricum yielded dauricoline (71) [C,,H,,N,O,; yellow powder; - 150"(MeOH)](42).The NMR showed the presence of three hydroxyl groups at 6 5.53 (exchangeable with D,O). Treatment with diazomethane gave t,he 0-methyl derivative (70) of dauricine (74). Final proof was provided by sodium-ammonia cleavage of O,O,Otriethyldauricoline, which yielded the two tetrahydroisoquinolines 29 and 75.
71 R, = R, = H 74 R1 = M e , R, = H 70 R, = R, = M e
5. BISBENZYLISOQUINOLINE ALKALOIDS
269
29 75
R = Et R = OH
0.0-DESMETHYLADIANTIFOLINE
+ 18") was isolated from the roots of Thalietrum minus f. datum (43).
I t s 0-methyl derivative, formed by reaction with diazomethane, was identical with adiantifoline (77). The position of the phenolic hydroxyl of 76 was revealed by permanganate oxidation of its 0-ethyl ether (from 76 and diazoethane), which afforded the known isoquinoline 78 and aldehyde 79, a known adiantifoline degradation product.
0-Desmethyladiantifoline (76) (C41H,,N20,; mp 125-126C;
[a],,
76 77
R = H R = Me
OMe
MeN
p::
0
78
79
270
M. P.
C A V A , K.
T. BUCK, AND K. L. STUART
P.
N'-DESMETEYLDAURICINE
N'-Desmethyldauricine (80) (C3,H,zN20,; amorphous; [ a ] : ' - 98'), rapidly discoloring on standing, was isolated from Menispermum cunudense L. ( 4 4 ) . Treatment with formaldehyde-sodium borohydride afforded dauricine (74), shown to have the R,Rconfiguration by comparison of the circular dichroism curve of its dimethiodide with that of an authentic sample. The location of the secondary nitrogen of 80 was shown by reaction with diazomethane and sodium-ammonia cleavage of the resulting 0-methyl derivative (81), which afforded ( - )-0-methylarmepavine (30) as the sole nonphenolic product.
80 81
R, = RP = H R, = Me, R2 = H 74 R, = H,R, = Me
&. 12'-O-DESMETHYLTRILOBINE
12'-O-Desmethj trilobine (82) [C34H,zN,05; mp 256-258C; [a (C,H5N)] was isolated from the stems of Anisocyclu grundidieri Baill. (45). Its structure was proven by correlation with the known related bases trilobine (83) and cocsuline (49). Thus, 0-methylation of 82 with diazomethane gave 83, whereas N-methyIation of 82 with formaldehyde-formic acid gave 49.
-t332"
5.
271
H,
R1 /
\
0
/
\
12
82
83
49
R, = R, = H R, = H, R, = Me R, = Me, R, = H
R. O,N-DIMETHYLMICRANTHINE
0,N-Dimethylmicranthine (12) (C,,H,,N,O,; mp 210-214C;
[.ID
- 241), was isolated from the bark of a Daphnandra sp. and Daphnandra
micrantha Benth. ( l 0 , I I ) . This alkaloid gave IR and mass spectra matching those of isotrilobine (50) but of opposite specific rot,ation, and 12 was identical with material prepared by N-methylating 0-methylmicranthine (84).
Me0
OMe
12 50 84
R = Me, chiral centers 1 and 1 = R (as shown) R = Me, chiral centers 1 and 1 = S R = H. chiral centers 1 and 1 = R
272
M. P. CAVA, K .
T.
BUCK, AND X. L. STUART
S. ( - )-EPISTEPHANINE
( - )-Epistephanine (85) [C,,H,,N,O,; mp 198-206C (MeOH); [.ID - 216" (CHCl,)] was isolated from the stems of Anisocycla grandidieri
(45). It was identical by NMR, UV, and I R with authentic (R)-( +)epistephanine (86), but its optical rotation was the opposite. It was therefore assigned structure 85.
Me0
85 Chird center = R (as shown) 86 Chirel center = S
T . ESPINIDINE
Espinidine (87)[C,,H42N206; amorphous; [.ID + 31" (CHCI,)] was isolated from Berberis laurina (46).Espinidine is a diphenolic base and is converted by diazoethane to an 0-ciiethyl derivative (88) and by diazomethane to an 0-dimethyl derivative; the latter was found to be identical with 0-trimethylespinine (89). Espinidine must therefore be an 0-methylespinine. Except for a very weak molecular ion a t m/e 610, the mass spectrum of 87 was practically identical with that of espinine, showing that the additional methyl group must be in the lower diphenyl ether portion of the molecule. Confirmation of structure 87 for espinidine was obtained by sodium-ammonia cleavage of its diethyl ether 88, which gave the two known benzylisoquinoline fragments 90 and 27.
MeN
H"
FoMe
OR
M " e0 " q N M ' ' . He
87 R = H 88 R = E t 89 R = Me
273
H*'
I"'H
27
90
U. ESPININE
Espinine (91) [C,,H,,N,O,; mp 123-125C; [a]= + 25" (CHCl,)] was isolated from Berberis laurina (46).It is a triphenolic base, giving an 0-trimethyl derivative (89) with diazomethane and an 0-triethyl derivative (92) with diazoethane. Espinine gives a very weak ( < 1%) molecular ion, characteristic of a dimeric benzylisoquinoline joined only in a tail-to-tail manner; the base peak a t m/e 192 reveals an N-methylisoquinoline unit bearing m e hydroxyl and one methoxyl. The structure 91 for espinine was assigned on the basis of the identification of the known monomeric benzylisoquinolines 90 and 56 as the sodiumammonia cleavage products of 0-triethylespinine (92).
91 R = H 92 R = E t 89 R = Me
56
90
274
M. P. CAVA, K.
T. BUCK,
AND K . L. STUART
V. FUNIFERINE
Funiferine (93) [C,,H,,N,06; mp 232-234C (EtOH) or 168-169C (MeOH); [elD + 171.4 (MeOH) or + 184.3 (CHCl,)] was isolated in 1965 from Tiliacora funifera Oliver ( T . warneckei ), although its structure could not be assigned a t that time (47). I t s NMR spectrum shows the presence of two N-methyls and four methoxyls. As a monophenolic base, funiferine is converted by diazomethane to 0-methylfuniferine (94)) which was shown by direct comparison t o be identical with the known 0-methylrodiasine. Conversion of funiferine t o 0-ethylfuniferine dimethochloride, followed by permanganate oxidation, afforded 2ethoxy-2-methoxy-5,5-dicarboxybiphenyl (95); the corresponding dimethoxydiacid (96) was obtained by oxidation of 0-methylfuniferine (94). Funiferine is therefore the positional isomer of rodiasine (97)) from which it differs only in the placement of the phenolic hydroxyl group in the biphenyl system. The structure was confirmed by a comparative mass spectral study of funiferine (93), rodiasine (97))and their common methyl ether (94). I n all cases, weak but significant ions were apparent that correspond t o the loss of the lower left-hand benzyl unit (cleavage a-b); ions corresponding t o the loss of the other half of the biphenyl unit (cleavage b-c) are not observed. The stereo-chemistry of funiferine cannot be assigned a t this time, although it must be the same as that of rodiasine (48).
93 R, = H, R, = Me 94 R, = R, = Me 97 R, = Me, Rz = H
OR
95 96
OMe
R = Et R = Me
5.
BISBENZYLISOQUINOLINE ALKALIODS
275
W. ISOTENWINE
Bark material from a Daphnandra sp. collected over thirty years ago mp 240C; [a];, in Australia yielded isotenuipine (98) [C,,H&&; + 129" (CHCI,); dimethiodide mp 278C (decornp.);5 A ] . [ - 50" (as)].
0-J
98
Placement of substituents was based on the fact that the mass spectrum shows an ion a t m/e 485 (M-151), indicating that the methylenedioxy is attached to ring E and also on NMR comparison with the structurally similar known bases (R)or (8)-tenuipine, tetrandrine, isotetrandrine, and phaeanthine. Evidence for the stereochemistry assigned was also based on a comparison of the specific rotation of isotenuipine with those of the above-mentioned bases.
X. 0-METHYLDAURICIXE
0-Methyldauricine (70) (C39H46N206; amorphous; [aID - 128") was isolated from Popowia cf. cyanocarpa Laut. and K. Schum. Its crystalline dimethiodide (mp 179-181C) was identical with material prepared from dauricine (74) by methylation (50).The bark of Colubrina asiatica Brongn. has also been found to contain 70 as the major alkaloid (51).
Me0
74 R = H 70 R = Me
276
M. P. CAVA, K. T. BUCK, AND K . L. STUART
Y. O-METHYLMICRANTHINE
O-Methylmicranthine (84) [C,,H,,N,O,; mp 163-165C (dec.); [cz]i0 -208"] from a Daphnandra sp. and D . micranthu was assigned its structure by direct correlation with micranthine, for which the correct structure 11 was reported a t the same time (11).The N-acetyl derivative - 203" (CHCI,). has mp 17P179"C (dec.);
Me0
OR
84 11
R =Me R = H
Z. NEMUARINE
Nemuarine (99) [C37H40N206; mp 222-223C; [.ID - 42.7" (CHCl,)] was isolated from the leaves of Nemuaron wieillardii Baill. (52, 53). Its mass spectrum shows intense ions a t M-213 and (M-212)/2,indicative of the loss of a diphenyl ether fragment from a head-to-head dimer molecule. Nemuarine is monophenolic and reacts with diazomethane to give O-methylnemuarine (loo), the mass spectrum of which indicates clearly that the phenolic function of 99 must reside in the diphenyl ether moiety. Sodium-ammonia cleavage of ether 100 gave (R)-Nmethylisococlaurine (28) and (R)-O-methylarmepavine (30). Prolonged heating of ether 100 with 3% DC1 in DzO a t 120C resulted in the introduction of one deuterium ; sodium-ammonia cleavage of the deuterated 100 gave undeuterated 28 along with the deuterated armepavine derivative 101, in which the shielded C, proton signal a t 8 5.98 had virtually vanished. Nemuarine was therefore established as structure 99 and represents the first example of a C,-C6. linked bisbenzylisoquinoline alkaloid. It appears to be derived biogenetically from two isococlaurine units.
5.
277
OMe
Me0
99 100
R=H R = Me
Me0
HO
30 R = H
101
L y
28
R =D
Pyenarrhena australiana F. Muell. afforded 2-N-norberbamine (102) [C36H38N206; mp 166-188C; [a]=+ 117" (CHCl,)] (54). FormaldehydeNBH methylation of it gave berbamine (103).Comparison of the NMR resonance of the N-methyl of 102 (6 2.62) with those of 103 "'-Me
6 2.65, N-Me 6 2.25 (55)] enabled the unambiguous assignment of
102
103
R =H R = Me
278
M. P.
C A V A , K. T. BUCK, AND
K . L. STUART
structure 102 to 2-N-norberbamine. Further support for this structure was provided by the mass spectrum which shows ions a t mle 192 (cleavage a-c) and 174 (cleavage b-c). BB. 2-N-NOROBAMEGINE The two Australian menispermaceous vines Pycnarrhena australiana (54)and Pycnarrhena ozantha (24)have been independently reported as sources of 2-N-norobamegine (104) [C35H3&&6; mp 188-190C (dec.) (CHC1, or acetone); [aID + 290" (CHCI,) (54) and [a]i5 - 146" (0.1 N HCl)] (24).N-Methylation of 104 gave obamegine (105) and subsequent treatment of this product with diazomethane afforded isotetrandrine (59). The structure and absolute stereochemistry of obamegine are known from cleavage experiments (56). The relative location of the secondary and tertiary nitrogens of 104 was revealed by the NMR spectrum, which shows a signal at 6 2.52, as expected for a 2'-N-methyl not subject to the shielding effect normally observed for the 2-N-methyl group in similar alkaloids (55) [S 2.27 for 2-N-methyl in 105 (54)].
104 105 59
R, = R2 = H
R, = Me, R, = H R, = R2 = M e
CC. NORTZIACORINE-A, NORTILIACORININE-A,

AND
NORTILLWORTNINE-B
Tiliacora racemosa Colebr. [synonymous with T.acuminata (Lam.) Miers] yielded the alkaloids nortiliacorinine-A [originally called pseudotiliarine (57)l [mp 262-268C (dec.) (acetone); [a]D + 268.8" (pyridine)] and nortiliacorinine-B [mp 218-220C (dec.) (acetone-MeOH); [.ID + 356.2" (pyridine)] (58). Tiliacora funifera (T. warneckei Engl. ex Diels) also afforded nortiliacorinine-A and, in addition, nortiliacorine-A [originally isotiliarine (57)l [mp 258-260C; [.ID + 194.5" (CHCI,)] (59). All three alkaloids were shown to possess the same molecular formula
5.
279
(C,SH3,N,0,). On N-methylation, nortiliacorine-A gave tiliacorine, while nortiliacorinine-A and nortiliacorinine-B afforded tiliacorinine. Tiliacorine and tiliacorinine are isomeric bases (C,,H,,N,O,) to which the partial structure 106 has been assigned from degradative and spectral studies (58). Thus, although more work is required to establish the substitution pattern and stereochemistry of nortiliacorinine-A, nortiliacorinine-B, and nortiliacorine-A, they may be assigned the preliminary structures 107 or 108.
OMe
OR3
106 107 108
0%
R, = Rz = Me, R, and R 4 I Me, H or vice versa R , = H, R, = Me, R, and R, = Me, H or vice versa R, = Me, R, = H, R1 and R , = Me, H or vice versa
DD. OXOEPISTEPHANINE
Stephnia hernandifolia Walp. afforded oxoepistephanine [C3,H,,N,0,; mp 22P226"C (dec.) (MeOH-ether);[ a ] : ' + 272" (CHCl,)] (60).The NMR spectrum was very similar to that of epistephanine (86), isolated from the same plant, except for a downfield shift of one of the aromatic resonances. The I R band at 5.97 p indicated a conjugated carbonyl and the mass spectral peak at mle 380 suggested that this was
380
109
280
M. P. CAVA, K. T. BUCK, AND K. L. STUART
86
located in the lower portion of the molecule. Structure 109 was proposed as most reasonable for oxoepistephanine; however, several attempts to interrelate chemicallythis alkaloid with epistephanine were unsuccessful.
EE. P A K I S T A N ~ N E
The first proaporphine-benzylisoquinoline dimer, pakistanamine (110) (C,,H,,N,O,), has been isolated from Berberis baluchistanicu as its picrate [mp 158-162C (dec.)]. The free base darkens readily to a deep purple color, but the hydrochloride [mp 215OC; [.I, + 20" (MeOH)] is fairly stable (61, 62).
H
a
1LO
UV, IR, and NMR data are in accord with structure 110, and mass spectrometry shows the major cleavagesa,b , and c . When pakistanamine was reduced with NBH, a mixture of diastereomeric dienols was produced. Acid treatment of this product with 3 N H2S04 afforded 1-0-methyl-10-deoxypakistanine (111) via a dienol-benzene rearrangement, while direct treatment of pakistanamine with 3 N HzS04resulted in a dienone-phenol rearrangement t o 1-0-methylpakistanine (112). Acetylation of the latter gave the corresponding acetate, and methylation yielded 1,lO-di-0-methylpakistanine (113).Catalytic reduction of pakistanamine hydrochloride with Pd/C afforded 11 ,lZ-dihydropakistanamine. ORD data are reported for most of these products.
5.
281
OMe
111 112
R =H R = OH 113 R = OMe
The occurrence of the alkaloids pakistanine and pakistanamine in t,he same plant lends substantial support to the earlier suggested biogenetic sequence (63): benzylisoquinoline --f bisbenzylisoquinoline --f proaporphine-benzylisoquinoline dimer + aporphine-benzylisoquinoline.
FF. PAEISTANINE
Pakistanine (114) [C3,H4,,N206; mp 15P-156OC; [a]g5 + 106' (MeOH)] was also isolated from Berberis baluchistanica (61, 62).The UV spectrum is similar to that of 9-phenylboldine, and the other spectral data are in accord with a linked aporphine-benzylisoquinoline structure. Sodium-
b
C
114 113
R = H R = Me
ammonia cleavage of the 0,O-dimethyl derivative 113 yielded (8)-( +)armepavine (115) and (R)-( - )-2,lO-dimethoxyaporphine (116). The presence of two phenolic hydroxyl groups in 114 was confirmed by the formation of an amorphous diacetate and by a bathochromic shift in the UV spectrum on the addition of base. The fact that pakistanine gave a negative test with phloroglucinol, a reagent that has been used to detect o-diphenols, was cited as evidence in partial support of
282
M . P.
C A V A , K.
T.
BUCK, AND
K . L. STUART
OMe
115
116
the placement of hydroxyl groups a t C, and Clo. That both phenolic groups were located on the aporphine moiety was fully corroborated by the mass spectrum of pakistanine, which shows ions a t m/e 402 (M-a), 312 (M-b), 296 (M-c), 206 (a, base ion), and 107 (cleavage at c and a). The NMR spectrum of 1-0-methyl-10-0-acetylpakistanine (prepared from 112) shows a one-proton singlet a t 6 8.21, whereas in 1,lO-di-Oacetylpakistanine, this proton experiences the upfield shift (to 6 7.73) expected for a C,, proton adjacent to a C, hydroxyl.
GG. PENDULINE
Penduline (117) (C3,H40N206;mp 192-194C; [aID + 265") was isolated from CoccuZus pendulus (syn. C. Zeaeba DC) (64).It forms the following crystalline salts: hydrochloride, mp 276-278C; picrate, mp 210-212OC; dimethiodide, mp 282-286C. As a monophenolic base, it reacted with diazomethane to give an 0-methyl ether and with diazoethane to give the 0-ethyl derivative. The mass spectrum of
117 118 64
R =H
R = Et R = Me
5.
283
penduline shows a characteristic head-to-head fragment at rnle 198 (doubly charged ion), showing that the free hydroxyl must reside in the diphenyl ether portion of the molecule. Sodium-ammonia cleavage of ethyl ether 118 gave (8)-0-ethylarmepavine (119)and (8)-N-methylcoclaurine (24). The structure 117 was therefore established for penduline.
119
24
Penduline is apparently the enantiomer of the known alkaloid pycnamine (65). Also, 0-methylpenduline (mp 150-152C; [.ID + 218"; hydrochloride, mp 272-275"C) picrate, mp 251-253OC) should be identical with tetrandrine (Sa). However, direct comparisons of these compounds were not reported.
HH. STEPINONINE
Stepinonine (120) [C36H34N20,; mp 24&245"C, 28OOC (dimorphism); [ a ] ; ' ' - 28" (pyridine)] was recently isolated from Stephania japonica Miers (66). The IR YE^ 3500 (OH), 1663 (C=O) cm-l] and NMR [ 6 5.60-7.37 (10 H-aromatic), 3.37, 3.85, 3.96 (3 OMe), 2.54 (N-Me)] revealed the functional groups present. Acetylation yielded a monoacetate and
OH
no
284
M. P.
C A V A , K. T. BUCK,
AND K . L. STUART
NBH reduction produced tetrahydrostepinonine, in which the disappearance of the corresponding band in the IR indicated reduction of the a,b-unsaturated carbonyl system. Treatment of the reduced compound with CH,O-NBH afforded the N-methyl derivative, which showed an abnormally high N-methyl NMR signal at 6 2.16, suggesting an unusual structure. N,O-Dimethyltetrahydrostepinonine (121) was cleaved with sodiumammonia to yield (8)-armepavine (115) and a hydro-3-benzazepine derivative, which was ethylated to give 122. The stereochemical assignments indicated for 122 were based on NMR data, and the identity of
OR
121 123
R = Me R = Et
115
122 125
0% R, = Et; R, = Me R1 = Me; R, = Et
this compound was firmly established by an unequivocal synthesis (67). The position of the OH group was established by KMnO, oxidation of N-methyl-0-ethyltetrahydrostepinonine (123) to the dicarboxylic acid
124.
The point of attachment of the second ether bridge (C, or C,) was revealed by deuteration experiments (C2H,0D-D,O, 307, DC1 a t 125130C for 100 hours) on N-methyl-0-ethyltetrahydrostepinonine fol-
5.
285
OEt
124
lowed by reductive fission to armepavine (115)and 125,deuterated at C, and C6,, respectively. The identity of 125 was established by comparison with racemic synthetic material (67).This new dimeric benzylisoquinoline-Z-phenyl-sec-homotetrahydroisoquinoline type could be biogenetically closely related to the rhoeadine-type alkaloids.
11. TELOBINE
Another new alkaloid which was reported from a Daphnandra sp. was named telobine (126)[C,,H,,N,O,; mp 185-195C (dec.); [ a ] ; ' + 188" (CHCl,)] (11). Telobine yielded the derivatives N-acetyltelobine [mp 180-185C (dec.);[a];, + 111" (CHCl,)] and N-methyltelobine (127)
H
Me
OMe
126 127
R =H R = Me
[C,,H,,N,O,, (M+ 576.2624); mp 175-180C (dec.); [a]h8 + 248" (CHCI,)]. NMR evidence indicated a diastereomeric relationship between N-methyltelobine (127)and 0,N-dimethylmicranthine (12); also, the properties of N-methyltelobine (mp and specific rotation) were in good agreement with those of a base structure 127 prepared by partial synthesis from oxyacanthine (68).
286
JJ. THALFINE
The novel structure 128 has been proposed for thalfine, [C38H,SN,08; mp 141-142C (dec.); [a]b5 + 69" (EtOH)] isolated from Thalictrum foetidurn L. (69).
OMe
I
4'
128
Two Hofmann degradations on thalfine dimethiodide produced trimethylamine, but in addition, a product that still contained nitrogen, suggesting the presence of an isoquinoline moiety in the structure. Reduction of thalfine dimethiodide with zinc in 20y0 H,SO, yielded N-methyltetrahydrothalfbe methiodide, which on treatment with ethanolamine gave N-methyltetrahydrothalfine. This product has an I R spectrum identical with that of another new alkaloid from the same plant, thalfinine (132), which is discussed in the next section. The substitution pattern of the lower portion of 128 was established by oxidation with KMnO, in acetone. The acid product afforded with diazomethane the dimethyl ester 129. Cleavage of thalfine with sodiumCO,Me
OMe
129
ammonia afforded the main products laudanidine (130) and 0methylarmepavine (131) of unspecified stereochemistry. The formation of 130 seems to be the result of an unexpected cleavage, perhaps resulting from the influence of the isoquinoline system. The placement of the other methoxyl and of the methylenedioxy group seems to be based mainly on NMR data. It is of interest to note that no mention was made of a quartet in the NMR spectrum expected
5.
287
130
R = OH 131 R = H
for the protons at C3, and C4, in ring D. Since no evidence is presented for the chirality of 130 and 131, no definitive assignment of configuration can be made for 128.
KK. THALFINDTE
Thalfinine (132) [C39H42N208; amorphous, mp 117-1 18C; [a]h6 (EtOH); perchlorate, mp 23P235"C (dec.); hydrochloride, mp 223-226C (dec.)] wits isolated from Thulictrum foetidurn (69). Its NMR showed two N-methyl groups (6 2.54, 2.30), four methoxyls (6 3.36, 3.43, 3.66 and 3.80), a methylenedioxy (6 5.80), and a C8H a t 6 5.92. As mentioned in the previous section, thalfinine was obtained from thalfine by N-methylation and reduction. The structure 132 has been proposed for thalfinine; however, no stereochemistry was assigned to either chiral center.
+ 115"
OMe
132
LL. THALICTROQAMINE
The alkaloid thalictrogamine (133),structurally related to thalicarpine (134), was isolated from Thulictrum polygamum Muhl. (70). Thalictrogamine (C3,H44N20,) an amorphous base [[a]g5 + 1 3 5 O
288
133 134 135
R, = Rz = H R, = R, = Me R1 = Me, R2 = H
(MeOH)] on treatment with diazomethane gave a mixture of thalictroThe mass spectrum [M+ 668, m/e 476 pine (135)and thalicarpine (134). (M-a), 326 (M-b), 309 (M-c-1), 192 (a, base)] provides evidence for the placement of one hydroxyl group on the tetrahydroisoquinoline ring B and the other on the aporphine moiety. From a study of space-filling models it was suggested that a C8. aromatic proton near 6 6.4, rather than near 6 6.2 in the NMR spectrum is diagnostic of the presence of a C7, phenolic substituent.
MM. THALICTROPINE
+ 120' Thalictropine (135) [C40H4,N,08; mp 167C (MeOH); (MeOH)] was recently isolated from Thalictrum polygumum (7'0).The presence of the phenolic group was evidenced by a bathochromic shift of the UV spectrum on the addition of base and by the preparation of thalictropine acetate (mp 182-183C). The NMR spectrum of thalictropine was superimposable upon that of 1-0-demethylthalicarpine synthesized in advance of its isolation
c
135
5.
289
from nature ( 8 ) .The mass spectrum [M+ 682, m/e 476 (M-a), 326 (M-b), 310 (M-c), and 206 (a, base peak)] clearly indicated that the phenolic hydroxyl was located on the aporphine residue.
113" (MeOH)] Thalidoxine (136) [C,,H,,N,O,; amorphous; from Thalictrum dioicum L. (71)is a substitutional isomer of thalictropine (135); accordingly, treatment with diazomethane yielded thalicarpine (134).
136 135 134 137
R, = H, R, = Me R, = Me, R, = H R, = R , = Me R, = Ac, R, = Me
Thalidoxine acetate (137) produced NMR evidence for the location of the hydroxyl a t Clz,. Although the Cll, proton was only slightly shifted (0.10 ppm) to lower field in 137 than in 136, there was observed a relative upfield shift of either 0.10 or 0.17 ppm in one of the aromatic resonances of 137, stated from inspection of molecular models to be possible for a C12, but not a Cll, acetoxylated system. NMR values are tabulated (71)for 136 and several other thalicarpinetype alkaloids. The mass spectrum of 136 shows the major fragmentations a, b, and c.
00. THALISOPIDINE
Thalisopidine (138) [C,,H,,NzO,; mp 215-216C; - 9" (EtOH)] was isolated from Thulictrum isopyroides C. A. Mey. (72). The NMR spectrum showed two N-methyl groups (6 2.44, 2.49), three methoxyls (6 2.96, 3.30, 3.70), and a C8, proton a t 6 6.30.
290
M. P. CAVA,
K.
T.
BUCK,
AND K . L. STUART
OH
MeN
\ /
138 139 0
/
\
RO
R =H R = Me
The structural assignment for thalisopidine is based solely on a comparison of its NMR with that of thalisopine (139);degradative, mass spectral, and NMR evidence exists in support of the structure suggested for this latter alkaloid (73).It is noteworthy, however, that no direct comparison was reported for 0,O-dimethylthalisopidine (mp 238-239C) and 0-methylthalisopine (amorphous; mp 163-166"C), which should be identical if the assigned structures 138 and 139 are correct.
PP. THALMELATIDINE
Thalmelatidine (140) [C42H48N2010; mp 120-122OC; [a]= + 47" (CHCl,)] was isolated from the roots of T h l i c t r u m minus f. elatum (74). Structure 140 was assigned to thalmelatidine on the basis of its NMR spectrum, as well as the formation of isoquinolone 141 and aldehyde 79 by permanganate oxidation. Aldehyde 79 was identical with the known aldehyde formed from adiantifoline (77)by a similar oxidation (43). Isoquinolone 141was synthesized from the known base 142by an unusual reaction sequence involving (a) bromination, (b) treatment with meth-
140
5.
291
MeN
@) A 0
0
141
MeN Meo 1
0
142
OMe
I
Me0
-NMe
U-
79
anolic sodium methoxide, (c) treatment with diazomethane, and (d) permanganate oxidation. The S,S configuration for 140 (shown below) was suggested as likely from its positive rotation and analogy with related alkaloids.
QQ. THALMINELINE
Thalmineline (143) [C,,H,,N,O,, ; mp 96-98C (ether-hexane) or mp 108-110C (EtOH); [aID + 22" (MeOH)]was isolated from the roots of Thalictrurn minus var. elaturn (75). Thalmineline is a phenol that has an unsubstituted position ortho or para to the hydroxyl function, since it not only gives a positive ferric chloride test but also couples with diazotized p-nitroaniline. Structure 143 has been assigned to thalmineline on the basis of NMR and mass spectral analogy with the related known bases thalicarpine (234) and adiantifoline (77). A salient feature of the NMR spectrum of 143 is the high field aromatic singlet at 6 5.7 1 , attributed to the C, aromatic proton. Also, the mass spectrum of 143 shows a base peak at rn/e 222, characteristic of an N-methyltetrahydroisoquinoline unit bearing two methoxyls and a hydroxyl. The possibility that the hydroxyl may be at C7, rather than a t C5, cannot be discounted, and the stereochemistry of 143 is apparently assigned by analogy with related bases.
292
M. P.
C A V A , K . T. BUCK,
AND K . L. STUART
143
134
R =H 77 R = OMe
RR. TRALRUUOSAMINE
280" Thalrugosamine (144) [C,7H,,N20,; mp 122-125C; (MeOH)]was isolated from Thalictrum rugosum Ait. (T. glaucum Desf.) (2'6). It was converted by diazomethane into O-methyloxyacanthine (145). The mass spectrum of thalrugosamine reveals a head-to-head fragment ion, mle 382, showing that the phenolic hydroxyl must be attached to an isoquinoline unit. Methyl ether 145, but not the parent alkaloid 144, shows a high field methoxyl signal a t 6 3.20 characteristic of a C,-methoxyl; the hydroxyl of 144 must therefore be a t C,. Chemical confirmation of structure 144 was obtained by diazoethane alkylation of thalrugosamine to give ethyl ether 146. Sodium-ammonia cleavage of 146 afforded the known monomeric bases 147 and 148, which were identical with reference samples (after methylation of 147).
5.
293
144 145 146
=H
R = ME R = Et
M~N;
m l I
'
147
mle 382
MeN H*' "H
OH
Me0
148
SS. THALRUBOSIDINE
(M+ 638); mp 172-174C; Thalictrum rugosum (77). Treatment with CH,N, yielded the known alkaloid thalidasine (18) previously isolated from this plant. The location of the phenolic group was established by sodium-ammonia cleavage of thalrugosidine ethyl ether,
Thalrugosidine (149) [C,,H,,N,O,,
- 185" (MeOH)] was isolated from
OR
Me0
149 18
=H R =Me
294
which gave compounds 150 and 20. Compound 150 was shown to be the optical antipode of a cleavage product derived from thalrugosine (151), while 20 was identical with the phenolic cleavage product of 18. Thalrugosidine is the substitutional isomer of thalfoetidine (19).
OH
150
20
TT. TRALRUGOSINE (77) [ = THALIGINE (78)l
+ 128" (MeOH)]was isolated from Thalictrum rugosum (77). Treatment
Thalrugosine (151) [C3,H40N20S, (M+ 608-2848); mp 212-214C;
[a]$0
of thalrugosine with CH2N, gave the monomethyl ether (mp 180182"C), which proved to be identical with isotetrandrine (59).
151 R = H 59 R = M e
The mass spectrum showed linked isoquinoline units at m/e 382-1877 and m/2e 191.0938 (cleavage at a), requiring the free OH to be in the top portion of the molecule. NMR data supported a C, located hydroxyl in that the spectrum of thalrugosine shows no methoxyl signal higher than 6 3.77, while compound 59 shows one a t 6 3.15. Sodium-ammonia cleavage of thalrugosine ethyl ether yielded 27, identified as its methiodide, and 24, identified by conversion to 0-
5.
295
'
27
OMe
24
R = H
15% R = Me
methylarmepavine (152) (IR, UV, thin-layer chromatography, and CD evidence). Thalrugosine has also been reported independently from T h l i c t r u m polygamum under the name thaligine [mp 153OC; + 87" (MeOH)] (78). Structural assignment was based on NMR, UV, ORD, and mass spectral data and conversion with CH2N2to 59. The identity of thalrugosine and thaligine has recently been established by direct comparison (79). The racemic form of 151 is the alkaloid cycleadrine (57).
UU. TOXICOFERINE
Toxicoferine (153) [C3,H3,N206;mp 286OC; [.ID - 263" ( 1 N HCI in EtOH)] was isolated from the stems of Chondodendron toxicoferum (Wedd.) Kruk. et Mold. (80). O-Ethylation of 153 with phenyltriethyl-
156
\
Y
157
J
153
296
M. P. CAVA, K. T.
BUCK, AND
K. L. STUART
ammonium ethoxide gave the amorphous 0-diethyl derivative, which was cleaved by sodium-ammonia to give (R)-N-methylcoclaurine (154) and racemic 0-diethyl-N-methylcoclaurine (155). The cleavage products
MeN
OH
'
154
155
OEt
indicate that toxicoferine (153) must be a molecular complex of ( - )-curine [ = chondodendrine (156)] and ( - )-tubocurine [ = ( - )chondrocurine (1571, the enantiomer of 31.
VV. TRICORDATINE
+ 247.9' Tricordatine (158) [C,,H,,N,O,; mp 280C (dec.); (pyridine)]was found in TricZisia subcordata Oliv. (35).The 0,O-dimethyl
PH
OH
158
dimethiohde derivative was shown to be identical with isotrilobine dimethiodide. Further support for the assigned structure 158 was provided by mass spectral data for 0,O-diethyltricordatine (M+ 604) and the 0,O-diacetate (M+ 632).
5 . BISBENZYLISOQUINOLINE ALKALOIDS
297
I V . Known Alkaloids from New Sources

Reference
45 81 82 83 84
Plant Anisocycla grandidieri Berberis lycium Royle Berberis petwlaris Nall. cyczea sp ( 9 ) Ephwtrum willosum (Exell) Troupin Mahonia aquifolium Nutt. Menispermum mnadense Pachygone pubeacens Benth. Pycharrhna australiana F. Muell. Stephania hernandifolia Walp. Stephania sasakii Hayata Thalictrumjlawum L. Thalictrum minus L.
Alkaloids Stebisimine, trilobine Berbamine (= berbenine) Berbamine Tetrandrine Cycleanine, isochondodendrine, norcycleanine Berbamine Daurinoline Isotrilobine Berbamine, isotetrandriine Epistephanine Berbamine Thalicarpine 0-Methylthalicberine, thalicberine, O-methylthalicberine, thalidazine Adiantifoline Adiantifoline, thalline Thalicarpine Thalidazine, thalsimine
85
44 86
54
60
87 88 89,90
43 91 71 90
Thalictrum minus f. elatum Thalictrum minus, race B Thalictrum polygamum Thalictrum rugosum
V. Methods and Techniques A. SPECTROMETRY

1. Mass Spectrometry
Mass spectrometry has now been established as one of the most important tools in the structure determination of bisbenzylisoquinoline alkaloids. The general aspects of its use have already been reviewed in Volume XI11 of this treatise. Three important papers have now appeared that extend and elaborate previous studies. In the first of these papers, detailed mass spectral data are presented for some simple alkaloid dimers derived from two coclaurine units joined tail to tail. Examples include molecules containing one, two, and three ether links; the head units (isoquinolines), when linked, all contain a C,-C,, ether bridge. Deuterated derivatives were used in a number of cases to support the proposed cleavage patterns (38). In the second paper, a similar analysis is made of alkaloids containing two ether bridges (head-to-head
298
M. P. CAVA,
K.
T. BUCK, AND K. L. STUART
and tail-to-tail linked) and containing head units linked by the more unusual C5-C,,, C,-c,#, and C,-C5, ether bridges (92). Finally, the last paper discusses the mass spectra of those alkaloids containing two ether bridges in which the monomer units are joined in a head-to-tail manner
(93).
2. Optical Rotatory Dispersion (ORD)
ORD curves have been recorded for a number of bisbenzylisoquinoline alkaloids. These include thalsimidine, thalsimine, hernandezine, thalisopine, thalmine, O-methylthalicberine, thalfoetidine, and fetidine (94)) as well as berbamunine and magnoline (95).
B. CHEMICAL METHODS
1. New Deuteration Procedures
A simple method for the preparation of O-trideuteriomethyl derivatives of phenolic alkaloids has been reported. The procedure involves use of a solution of diazomethane in dimethyl sulfoxide containing D,O ( 1 1 ) . The selective introduction of deuterium into bisbenzylisoquinolines has been accomplished by heating with 3 7 , DC1 in D,O a t 120C for 144 hours. Under these conditions, O-methyloxyacanthine (145) exchanged all protons ortho t o methoxyl groups (but none ortho t o the diphenyl ether bridges), as shown by subsequent cleavage of the deuterated derivative (159)to 160 and 161; the location of deuterium in the cleavage products was readily established by NMR spectroscopy (96). However, extension of this deuteration procedure t o the newly isolated alkaloid nemuarine (99) resulted in the introduction of only one deuterium, a t position C, (52, 53). It thus appears that' the location of the ether bridging, the stereochemistry, and the substitution pattern of the system govern the extent to which deuterium is incorporated. Further work is clearly needed to evaluate these factors, as well as t o extend the utility of this method of deuteration in structural elucidation. The utility of the sodium-ammonia cleavage of bisbenzylisoquinoline alkaloids as a tool for structure proof has been extended by utilization of ND, rather than NH,. Since deuterium is introduced at the points of cleavage of the diphenyl ether linkages, this variation provides additional information of particular advantage for alkaloids containing two ether bridges, as in the case of belarine (25) ( 2 1 ) . ND, may be conveniently prepared from D,O and Mg,N, (28). In the case of alkaloids containing one secondary and one tertiary
299
MeN
R
145 159
R =H R =D
MeN
160
OH
D
161
amine function, treatment with formaldehyde-d, and NBD introduces a trideuteriomethyl group on the secondary nitrogen. Oxidative photolysis (see next section) and NMR studies of the products may then be used to establish the nitrogen alkylation pattern of the original alkaloid ( I 0 , I I ) . Use of this procedure made possible the assignment of the correct structure t o micranthine (11).
2 . Photooxidative Degradation
Sodium-ammonia cleavage has long been the dominant method for the chemical degradation of bisbenzylisoquinoline alkaloids. Oxidation procedures have been of limited utility in the past and have seldom resulted in the isolation of fragments derived from all parts of the original alkaloid. A mild photooxidative degradation has been reported recently that promises to complement sodium-ammonia cleavage as a general degradative method for bisbenzylisoquinoline alkaloids (97). I n a model case, isotetrandrine (59) was irradiated with a Hanovia lamp in dilute methanol solution at room temperature in the presence of
300
M. P. CAVA, K .
T. BUCK,
AND K . L. STUART
oxygen. The diphenyl ether portion of the molecule was isolated directly as the dialdehyde 14 in 50y0 yield. After borohydride reduction, the crystalline head-to-head isoquinoline fragment 162 could also be isolated. Phenolic alkaloids also seem amenable to photooxidative degradation. For example, berbamine (103) gave the phenolic aldehyde 163 (35%) as well as the lactam base 162 (15%).
59 103
R = Me R =H
162
14
R =Me
R =H
163
VI. Pharmacology
Thalidasine and obamegine were found to be active in vitro against Mycobacterium smegmatis; thalrugosine, thalrugosamine, and thalrugosidine were all very weakly active against the same organism (7'6, 77, 98). Tetrandrine showed strong tuberculostatic activity against a number of strains of Mycobacterium tuberculosis in vitro; it also found to significantly prolong the life expectancy of mice infected with various tuberculosis strains (99). Thalsimine, dihydrothalsimine, and hernandezine were found to inhibit the conditioned avoidance reactions and the motor conditioned reflexes associated with movement and eating in rats. In addition,
5.
301
thalsimine and dihydrothalsimine were found to temporarily reduce the time for dogs to run through a labyrinth (100). The tertiary bases tetrandrine, cycleanine, and dauricine exhibited antiinflammatory and anesthetic properties; the related quaternary salt cycleanine dimethiodide was a curare-like agent (101). Thalmine and 0-methylthalicberine were active against experimental idammation in mouse paw (102). The cardiovascular and hypotensive activity of thalicarpine has been studied in the isolated dog heart and in the rhesus monkey. Thalicarpine hypotension appears to be due to a nonspecific vasodilation and myocardial depression (103).Fetidine is claimed to have hypotensive activity (104). Both thalisopine and fetidine depress high nervous activity in mice (105). The toxicity of thalicarpine has been examined in monkeys and in dogs. Lethal doses in monkeys and maximum nonlethal doses in both species were determined (106). The alkaloids thalicmine, dihydrothalicmine, hernandezine, thalmine, thalictrinine, and fetidine were more active against experimental inflammation than either aminopyrine or sodium salicylate (107).
VII. Bisbenzylisoquinoline Alkaloids Tabulated by Molecular Weight

This table includes all reported bisbenzylisoquinoline alkaloids ; references are to the most recent compilation in which each alkaloid is discussed. Molecular weights cited for alkaloids that have not been examined by mass spectrometry must be regarded as provisional unless corroborated by synthetic studies. Also, assignments based on correlation with alkaloids of subsequently revised structure (e.g.,micranthine) should be considered questionable.
MW Formula Alkaloid Ref. ( M W
a a a a
a
a
Formula
Alkaloid
Ref.
548 C34H3zNz05 12-O-Desmethyltrilobine Micranthine Tricordatine 562 C,SH,,NzO, Cocsuline ( 2 trigilletine, effirine) 0-Methylmioranthine Nortiliacorine-A Nortiliacorinine-A Nortilimorinine-B
566 576 576
a a
578
Telobine Trilobine C34H34Nz06N,N-Bisnoramoline C35H3zNz06Normenisarine C36H3SNz0s 0,N-Dimethylmicranthine Isotrilobine Tiliacorine Tiliacorinine C35H,4Nz0s No name
b
a
(conrinued )
302
MW Formula
Alkaloid
Ref.
MW
Formula
Alkaloid
Ref.
C
-~
580 C35H36N206Cycleacurine Daphnoline ( = trilobamine) 2-N-Norobamegine 582 C35H38NzO6 Ocotine 590 C36H34Nz06 Menisarine Stebisimine 592 C36H36N206Cepharanoline Hypoepistephanine Thalmethine Tiliarine 594 C36H38N206Aromoline Atherospermoline Base A Chondrocurine Curine ( F bebeerine, chondrodendrine) Daphnandrine Demerarine Dinklageine Dryadodaphnine Hayatine (= ( & ) ~urine] Isochondrodendrine Neoprotocuridine 2-N-Norberbamine Obamegine Ocoteamine Protocuridine Sepeerine Thalicrine Tomentocurine Toxicoferine 596 C36H40Nz06 Berbamunine Dauricoline Espinine Magnoline 606 C36H34N207 Stepinonine Cancentrine 606 C3.,H3,NZ06 Cepharanthine Cissampareine Coclobine Epistephanine ( - )-Epistephanine
a c a
C
b
a
C
b
C C
b d
&
b
e
b
b d a
C
d
C
e d a b a
a
b a a b b b b a
Insulanoline 0-Methylthalmethine ( = thalmidine) 608 C37H40N206Belarine Berbamine Chondrofoline Cycleadrine Cycleanorine Cycleapeltine Dryadine Fangchinoline Hayatidine Hayatinine Himanthine Homoaromoline Homothalicrine Lauberine Limacine Limacusine Menisidine 4"-O-Methylbebeerine Nemuarine Norcycleanine Ocodemerine 0tocamine Oxyacanthine . Pakistanine Penduline Pycnamine Repandine Thalicberine Thalmine Thalrugosamine Thalrugosine (= thaligine) 609 C37H41N20t Protochondrocurarine Tubocurarine 610 C37H42N206 Cuspidaline Dauricinoline Daurinoline N'-Desmethyldauricine Dirosine Espinidine
a b
a a
a a b b b b
e
C
e
b b b d b a
C
b b b a a b b b b a a
e
a b a b
&
b a
5.
MW Formula
303
Alkaloid Ref.
Alkaloid
Ref. b b b d b b d a b
C
MW
Formula
612 612 616 620 620 622
622
Isoliensinine Liensinine Norrodiasine C35H36Nz08 Base B C36H40Nz07Aztequine Magnolamine C38H36N20~ Phaeantharine C37H36Nz0, Oxoepistephanine Repanduline C38H40N206Insularine C3,H38N207 De-N-methyltenuipine Nortenuipine Thalsimidine C38H42Nz08 Cycleanine (= O-methylisochondroden+
d
C
b b
drine
Funiferine Isotetrandrine Melanthioidine Menisine 0-Methylisothalic berine 0-Methylrepandine 0-Methylthalicberine Obaberine Pakistanamine Phaeanthine Rodiasine Tetrandrine C3,H4,Nz0, Thalidopidine C38H44N206 Dauricine C38H44Nz0z +Chondrocurarine Isochondrocurarine Neochondrocurarine C3,H4,NzOS Pycnarrhenamine
a b b d b d b b a b b b a b a e e b
624 624 624
632
636 C38H40N20, Isotenuipine a Repandinine (= (k). d tenuipine) Tenuipine C Thalsimine b 637 C39H45NzOs+ Cycleahomine a 638 C38H42N207 Thalfoetidine a Thalidezine b Thalisopine b Thalrugosidine a 638 C39H4BN206 0-Methyldauricine a Neferine b e 642 C38H46N207 Thalictrinine b 646 C36H42N209 Pycnarrhenine 648 C38H36N208Thalfine a b 652 C39H44N207 Hernandezine Thalidasine b 666 C39H42N208 Thalfinine a b 668 C39H44N208b Thalibrunine a Thalictrogamine a 674 C40H38N20i +Bisjatrorrhizine b 680 C40H44N208 Dehydrothalmelatine a 682 C40H46N208 Thalictropine a Thalixodine C Thalmelatine b 694 C41H46N208 Dehydrothalicarpine a 696 C41H48N208Fetidine b Thalicarpine b 698 C40H46N20s Thaldimerine a 712 C41H48N209 O-Desmethyladiantifoline a 720 C43H32N209 Chelidimerine b 726 C42H50N209 Adiantifoline a 740 C42H48NZ010 Thalmelatidine a 742 C42H50Na0~0 Thalmineline
References; (a) This work. (b) M. Curcumelli-Rodostamo, in The Alkaloids (R. H. F. Manske, ed.), Vol. XIII, Chapter 7. Academic Press, New York, 1971. (c) M. Curcumelli-Rodostamo and M. Kulka, in The Alkaloids (R. H. F. Manske, ed.), Vol. I X , Chapter 4. Academic Press, New York, 1967. (d) M. Kulka in The Alkaloids (R. H. F . Manske, ed.), Vol. VII, Chapter 21. Academic Press, New York, 1960. (e) T. Kametani, The Chemistry of the Isoquinoline Alkaloids, Chapter 6 . Elsevier, Amsterdam, 1969. Corrected molecular formula; the formula cited in reference b is in error due to a n internal inconsistency in the original paper.
304
VIII. Appendix
It is the function of this appendix to abstract papers on bisbenzylisoquinoline alkaloids that appeared in 1974 and the first half of 1975, as defined by the Chemical Abstracts coverage stated in Section I, and also amend the text. The structural formulas, basic physical constants, and plant sources of new alkaloids are noted, but the reader is referred to the original papers for details of structural elucidation. It is intended that material included here will be incorporated in expanded form in an appropriate later volume of this treatise. This appendix has been organized in conformity with the plan of the foregoing main discussion, and a miscellaneous section has been included to draw attention to some interesting transformations of particular alkaloids that were recently reported.
1.
NEW ALKALOIDS
a. Sanguidimerine (164)
T h i s alkaloid [mp 174C; +21.2O (pyridine)] was isolated from rhizomes of Sanguinam'a canadensis L. and is diastereomeric with the meso alkaloid chelidimerine (46) (108). These natural products along with 48 are the first representatives of the class of bisbenzophenanthridine alkaloids and are included in our review because of their dimeric nature and their formal 4-phenethylisoquinoline structure unit.
164
5.
305
b. Cocsulinine (165) Cocsulinine [mp 260-263OC; [.ID + 312" (CHCl,)] was isolated from Cocculus pendulus (108)and possesses anticancer activity. The structure was assigned from spectral data, deuterium exchange experiments, Hofmann degradation, and sodium-ammonia cleavage.
165
c. Cocsoline (166) Isolated also from Cocculus pendulus (110) was cocsoline [mp 197199C; [.ID + 204" (CHCl,)]; it was assigned st,ructure 166 on the basis of MS and NMR data and conversion to isotrilobine (50).
AH
166
d. Tiliageine (167)
+ 132.6" (pyridine)] (111).The structural assignment was based on IR

and NMR data and conversion to O-methylfuniferine (94). The stereochemistry is still undetermined.
Tiliacora dinklagei Engl. has yielded this alkaloid [mp 270C;
306
M. P. CAVA, K.
T.
BUCK, AND K . L. STUART
167
e. Pennsylpavine (168) and Pennsylpavoline (169)
Thalictrum polygamum afforded the first two aporphine-pavine dimers; pennsylpavine (168) [mp 122-123C; [a]g5 - 174" (MeOH)]and pennsylpavoline (169) [mp 145-146C; [a]g5 - 245" (MeOH)].Structural assignments were based entirely on spectral data (UV, NMR, mass, CD). The related alkaloids pennsylvanine (170) and pennsylvanamine (171) were also reported from T . polygamum (112).
f. Pennsylvanine (170) and Pennsylvanamine (171)
The chemical and spectral data leading to the structures of these two new alkaloids have now appeared (113):pennsylvanine (170) [mp 112113C (ether); [a]g4 + 131" (MeOH)] and pennsylvanamine (171) [mp 128-129C (acetone-ether), 107-108C (ether); + 119" (MeOH)].
170 171
R R
= Me =H
168 R = Me 169 R = H
5.
307
g. Monomethyltetrandrinium Chloride (172)

The Thai Menispermaceae drug krung kha mao yielded this alkaloid [mp 208C; [a]gO + 51.5" (MeOH)] (114).T h i s new berbamine alkaloid was assigned structure (172)based on spectral data and partial synthesis from tetrandrine (64);the nitrogen methylation pattern was not established.
OMe
172
R = H, R, = Me, or vim versa
h. Baluchistanamine (173) Baluchistanamine (173)[mp 122-124C (cyclohexane-benzene)] has c a . data are given for this been reported from Berberis b a ~ u ~ h i ~ t a n iCD first example of an isoquinoline-benzylisoquinoline type of alkaloid (115).
173 174
R =H R = Me
MeN H
pL
OMe
38 176
R = Me R =H
308
M. P.
C A V A , K. T. BUCK, AND
K. L. STUART
Oxidation of obaberine (38) with KMnO, in acetone afforded 0methylbaluchistanamine (174), while corresponding treatment of oxyacanthine (175) gave 173 in low yield. Apparently, 173 arises biogenetically from the cooccurring oxyacanthine (175).
i. Phlebicine
Cremastosperma polyphlebum (Diels) Fries yielded phlebicine (176) (mp 195C; sint, 180"C), for which ORD and CD data are given. Partial methylation of 176 afforded rodiasine (97) and NMR and MS comparisons of 176 and its dideuterio, deuteriomethyl, 0-acetyl, and 0-ethyl derivatives permitted unambiguous assignment of its skeleton (116).The stereochemistry of the asymmetric centers, however, is not yet determined.
176
97
R =H R = Me
j. Thalibrunine (177) Thalibrunine (177) from Thalicfrumrochebruniannum Franch. e t Sav. has been assigned the structure shown on the basis of chemical and spectral data (117).
MeN N
M OMe e
&
f
-*
177
5.
309
2. KNOWN ALKALOIDS FROM NEW SOURCES

Reference 118 118 118 119 120 Plant
~ ~
Alkaloids
-
121
Triclisia gillettii 27. patens Oliver T . subcordata Anisocycla grandidieri Cyclea barbata Miers (C. peltata Hk. f. et. Thorns). C. barbata
Stebisimine, isotetrandrine, cocsuline (49) Pycnamine, cocsuline (49) Fangchinoline, tricordatine ( -)-Epistephanine (85), stebisimine ( + )-Tetrandrine,isotetrandrine, limacine, berbamine, homoaromoline
( & )-Fangchinoline, (
+ )-isofangchinoline
[thalrugosine (151)]
3. PHARMACOLOGY
Kupchan and Altland (122) have made a study of the structural requirements for tumor-inhibitory activity among bisbenzylisoquinoline alkaloids and related compounds. Pharmacological evaluations of a number of bisbenzylisoquinolinealkaloids and synthetic analogs against Walker carcinosarcoma 256 in rats were used to study structural requirements for therapeutic activity. Only one linkage of the isoquinoline unit appears necessary, and activity is seemingly unaffected by the configuration of the asymmetric centers or whether the nitrogens are secondary or tertiary. However, the presence of two methylimino groups destroys activity. Thalmine has been shown to be significantly active against ascites lymphoma NK/Ly in mice and rats. Thalsimine, thalmidine, thalictrinine, and hernandezine were weakly active against lymphoma NK/Ly, alveolar hepatoma PC-1, or Pliss lymphosarcoma (123). Two new reports of antimicrobial studies have appeared. Thalicarpine isolated from Thalictrum polygamum was shown to be active against Mycobacterium smegmatis but not against five other bacterial species (124). Extracts of Berberis vulgaris have been examined for antibiotic activity; oxyacanthine chloride a t 1 :10,000 dilution killed Bacillus subtilis and Colpidium colpoda (125). The effects of thalicarpine on the heart and carotid artery flow in anesthetized monkeys and on isolated dog hearts has been studied. The principal activity seemed to reside in the aporphine portion of the molecule (126). The action of hayatine methochloride and ( + )-tubocurarine chloride
310
M. P. CAVA, K . T.
BUCK, AND
K . L. STUART
on autonomic ganglia in cats has been examined. Hayatine methochloride was 2.5-4 times less active than tubocurarine chloride on sympathetic ganglia of cats. Details are given in the Chemical Abstract (127). . . Toxicity studies by Menez et al. (128) on (+)-tubocurarine labeled with iodine or tritium showed that tritium in the 13 position had no effect on its acute toxicity. Tubocurarine chloride, when given intravenously to rabbits or subcutaneously to rats, induced hypercalcemia and hypophosphatemia but did not affect blood pH (129). The lymphotoxic effect of d-tetrandrine in dogs and monkeys has been demonstrated, as was related toxicity levels on these test animals (130). Phaeanthine, isolated from Phaeanthus ebracteolatus, has been shown to have anticancer activity, and in a review of the chemistry and biochemistry of alkaloids from this plant, this property was discussed in relation to structurally similar bisbenzylisoquinolines (131). The neuromuscular blocking potencies of ( + )-tubocurarine chloride, N,N-dimethyl-( + )-chondrocurine and N,N-dimethyl-(- )-curine have been evaluated on rat diaphram, cat tibiales, and superior cervical ganglion (132). I n another related study, the same authors (133) examined five bisbenzylisoquinolines that have head-to-head and tailto-tail linkage and were shown to have negligible blocking action on cat tibiales and superior cervical ganglion in relation to ( + )-tubocurarine. N,N -Dimethylberbamine, however, showed substantial activity.
4.
MISCELLANEOUS
a. Hofmann Elimination Effected by Diazomethane When the quaternary curare bases ( + )-tubocurarine chloride (l), ( + )-isotubocurarine chloride (178), and chodrocurarine chloride (4) were treated with excess diazomethane, in addition to the expected O-methyl derivatives, the respective Hofmann elimination products (179), (180), and (181) were also produced (134). The nature of the products (styrene versus stilbene) is apparently governed by steric factors. b. Conversion of Stepinonine (120) into a Conventional Bisbenzylisoquinoline Skeleton As a sequel t o their full account of the structural elucidation of the novel benzylisoquinoline-2-phenyl-sec-homotetrahydroisoquinoline
5.
311
1 178
R1 = Me, R, = H (Cl-)
179
R1 = H, R, = Me (Cl-) 4 R, = R, = Me (Cl-)
M e 0e
N .H M
Me,N
180
181
alkaloid, stepinonine (135), Inubushi and co-workers have succeeded in a chemical conversion of stepinonine to identifiable bisbenzylisoquinoline alkaloids (136). Stepinonine (120) was first converted to its reduced derivative (121) and then oxidation by Jones' reagent followed by reduction (zinc-acetic acid, then sodium borohydride) gave a mixture of the enantiomer (68) of 0-methylrepandine and O-methyloxyacanthine (145).
312
68
MeN
OMe Me
H '
H '
145
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5.
315
73. Kh. G. Pulatova, S. Kh. Maekh, 2. F. Ismailov, and S. Yu. Yunusov, Khim. Prir. Soedin. 4, 394 (1968); C A 7 0 , 88033 (1969). 74. N. M. Mollov and Le Nhat Thuan, Dokl. Bolg. Akad. Nauk. 24, 601 (1971); C A 7 5 , 106055 (1971). 75. J. Reisch, H. Alfes, T. Kaniewska, and B. Borkoswki, Tet. Lett. 2113 (1970), 76. L. A. Mitscher, W.-N. Wu, and J. L. Beal, Ezpel-ientk 28, 500 (1972). 77. L. A. Mitscher, W.-N. Wu, R. W. Doskotch, and J. L. Beal, LZoydia 35, 167 (1972); C A 77, 98905 (1972). 78. M. Shamma and S. Y. Yao, Ezperientk 29, 517 (1973). 79. Private communication. We thank Professors Shamma and Beal for making this comparison. 80. M. P. Cava, J. Kunitomo, and A. I. daRocha, Phytochemistry 8 , 2341 (1969); C A 72, 97303 (1970). 81. 0. A. Miana, M. Ikram, and S. A. Warsi, Pak. J. S c i .I d . Reg. 12, 159 (1969); C A 72, 55716 (1970). 82. G. A. Miana and M. Ikram, Pak. J. Set. I d . Res. 13, 49 (1970); C A 73, 117192 (1970). 83. C. Goepel, S. von Kuerten, T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 22, 402 (1972); C A 78, 69230 (1973). 84. A. Bouquet and A. Cave, Plant Med. Phytother. 5 , 131 (1971); C A 75, 85207 (1971). 85. P. P. Panov, N. M. Mollov, and L. N. Panova, Dokl. Bolg. Akad. Nauk 24, 675 (1971); C A 7 5 , 148465 (1971). 86. N. K. Hart, S. R. Johns, J. A. Lamberton, and H. Suares, A w t . J. Chem. 25, 2289 (1972). 87. J. Kunitomo, Y. Okamoto, E. Yuge, and Y. Nagai, Yakugaku Zasshi 89, 1691 (1969); C A 73, 4072 (1970). 88. Kh. S. Umarov, 2. F. Ismailov, and S. Yu. Yunusov, Khim. Prir. Soedin. 6 , 444 (1970); C A 74, 1042 (1971). 89. Kh. B. Duchevska, A. V. Georgieva, N. M. Mollov, P. P. Panov, and N. K. Kotsev, Dokl. Bolg. Akad. Nauk 24, 467 (1971); C A 75, 106101 (1971). 90. N. M. Mollov, P. Panov, Le mat Thuan, and L. Panova, Dokl. Bolg. Akad. Nauk 23, 181 (1970); CA 73, 32285 (1970). 91. C. W. Geiselman, S. A. Gharbo, J. L. Beal, and R. W. Doskotch, Lloydia 35, 296 (1972); C A 7 8 , 13766 (1973). 92. J. Baldas, I. R. C. Bick, M. R. Falco, J. X. DeVries, and Q. N. Porter, J. Chem. SOC., Perkin Trans. 1 5 9 7 (1972). 93. J. Baldas, I. R. C. Bick, T. Ibuka, R. S. Kapil, and Q. N. Porter, J . Chem. SOC., Perkin Trans. 1 5 9 9 (1972). 94. G. P. Moiseeva, 2. F. Ismailov, and S. Yu. Yunusov, Khim. Prir. Soedin. 6 , 705 (1970); C A 74, 112278 (1971). 95. T. Kametani, H. Iida, K. Sakurai, S. Keno, and M. Ihara, Chem. Phurm. Bull. 17, 2120 (1969); C A 72, 32092 (1970). 96. Y. Inubushi, T. Kikuchi, T. Ibuka, and I. Saji, Tet. Lett. 423 (1972). 97. I. R. C. Bick, J. B. Bremner, and P. Wiriyachitra, Tet. Lett. 4795 (1971). D 589 98. L. A. Mitscher, W.-N. Wu, R. W. Doskotch, and J. L. Beat, J. Chem. SOC. (1971). 99. S . A. Vichkanova, L. V. Makarova, and L. F. Solov'eva, Farmakol. ToksikoZ. (Moscow) 36, 74 (1973); CA 78, 106079 (1973). 100. N. Tulyaganov and F. Sadritdanov, Farmakol. Alkaloidov. Serdechnykh Glikozidwv 132 (1971); C A 78, 79631 (1973).
316
101. V. V. Berezhinskaya, Postep Dziedzinie Leku Rosl., P r . Ref. Dosw. Wygloszone Symp., 1970 164 (1972); C A 7 8 , 119087 (1972). 102. F. Sadritdinov and M. B. Sultanov, Farmakol. Alkaloidow Serdechnykh Glikozidov 120 (1971); C A 7 8 , 66916 (1973). 103. E. H. Herman and D. P. Chadwick, Toxicol. Appl. Pharmacol. 26, 137 (1973). 104. Zh. S. Nuralieva and P. K. Alimbaeva, Fizwl. Akt. Soedin. Rust. Kirg. 99 (1970); C A 7 6 , 17765 (1972). 105. I. Khadamov, F. Sadritdinov, and M. B. Sultanov, Farmakol. Alkaloidov Serdechnykh Glilcozidov 135 (1971); C A 7 7 , 122095 (1972). 106. P. E. Palm, M. S. Nick, E. P. Arnold, D. W. Yesair, and M. M. Callahan, U.S. N.T.I.S. P B Rep. PB-201 914 (1971); C A 7 6 , 68093 (1972). 107. F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Olikozidov 122 (1971); C A 7 8 , 79555 (1973). 108. M. Tin-Wa, H. H. S. Fong, D. J. Abraham, J. Trojanek, and N. R. Farnsworth, J . Pharm. Sci. 61, 1846 (1972). 109. P. P. Joshi, D. S. Bhakuni, and M. M. Dhar, Indian J. Chem. 12, 517 (1974); C A 81, 136346 (1974). 110. P. P. Joshi, D. S. Bhakuni, and M. M. Dhar, Indian J. Chem. 12, 649 (1974); C A 81, 152477 (1974). 111. A. N. Tackie, D. Dwuma-Badu, T. T. Dabra, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Experientia 30, 847 (1974). 112. M. Shamma and J. L. Moniot, J. A m . Chem. SOC. 96, 3338 (1974). 113. M. Shamma and J. L. Moniot, Tet. Lett. 2291 (1974). 114. B. Hoffstandt, D. Moecke, P. Pachaly, and F. Zymalkowski, Tetrahedron 30, 307 (1974). 96, 7809 (1974). 115. M. Shamma, J. E. Foy, and G. A. Miana, J. A m . Chem. SOC. 116. M. P. Cava, K. Wakisaka, I. Noguchi, D. L. Edie, and A. I. daRocha, J. Org. Chem. 39, 3588 (1974). 117. M. P. Cava, J. M. Saa, M. V. Lakshmikantham, M. J. Mitchell, J. L. Beal, R. W. Doskotch, A. Ray, D. C. DeJongh, and S. R. Shrader, Tet. Lett. 4259 (1974). 118. A. N. Tackie, D. Dwuma-Badu, T. Okarter, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Lloydia 37, 1 (1974). 119. A. Groebe1,H. Kruse, and N. Weber, German Patent 2,243,253 CA 81, 6264 (1974). 120. T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 25, 315 (1974); C A 81, 82289 (1974). 121. C. Goepel, T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 26, 94 (1974); C A 81, 87983 (1974). 122. S . M. Kupchan and H. W. Altland, J. Med. Chem. 16, 913 (1973). 123. Sh. U. Ismailov and D. A, Asadov, Parmakol. Alkaloidow Ikh. Proizvodnykh 171 (1972); C A 80, 103857 (1974). 124. S. A. Gharbo, J. L. Beal, R. W. Doskotch, and L. A. Mitscher, Lloydia 36, 349 (1973); C A 80, 12512 (1974). 125. E. Andronescu, P. Petcu, T. Goina, and A. Radu, Clujul Med. 46, 627 (1973); C A 81, 100062 (1974). 126. E. H. Herman and D. P. Chadwick, Pharmacology 10, 178 (1973). 127. G. K. Patnaik, S. N. Pradhan, and M. M. Vohra, Indian J. E z p . Biol. 11, 89 (1973); C A 80, 103855 (1974). 128. A. Menez, F. Bouet, J. P. Changeux, A. M. Rousseray, P. Boquet, and P. Fromageot, Biochimie 55, 919 (1973); CA 80, 116086 (1974). 129. P. Szabo andT. Ferenczy, Acta Biol. Debrecina9, 101 (1973);CA 81, 114747 (1974).
5.
317
130. E. J. Gralla, G. L. Coleman, and A. M. Jonas, Cancer Chenwther. Rep,, Part 3 5 79 (1974); C A 82, 51463 (1975). 131. A. C. Santos, Acta Manilam, Ser. A 12, 48 (1974); C A 82, 95236 (1975). 132. I. R. C. Bick and L. J. McLeod, J . Phurm. Pharmacol. 26, 985 (1974). 133. I. R. C. Bick and L. J. McLeod, J . Phurm. Pharamcol. 26, 988 (1974). 134. J. Neghaway, N. A. Shaath, and T. 0. Soine, J . Org. Chem. 40, 539 (1975). 135. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 23, 114 (1975). 136. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 23, 133 (1975).
-CHAPTER
6---
SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

MAURICESHAMMA
The Pennsylvania State University
University Park, Pennsylvania
AND
VASSILST. GEORGIEV
U S V Pharmaceutical Corporation Tuekahoe, New York
I. Introduction. .... .............................................. 1 1 . Dauricine-Type A1 oids ........................................... 1 1 1 . Magnolamine-Type Alkaloids. ....................................... IV. Berbamine-Oxyacanthine-TypeAlkaloids. . . ...................... V. Thalicberine-Type Alkaloids . . . . . . . . . . . . . . ...................... VI. Trilobine-Isotrilobine-Type Alkaloids . . . . . . ...................... VII. Menisarine-Type Alkaloids .......................................... VIII. Tiliacorine-Type Alkaloids ....................... ................ I X . Liensinine-Type Alkaloids ....................... ................ X. Curine-Chondocurine-TypeAlkaloids. ................................ XI. Miscellaneous Syntheses ............................................ XII. Syntheses Using Phenolic Oxidative Coupling ......................... X I I I . Synthesis Using Electrolytic Oxidation. ....................... .. XIV. Use of Pentafluorophenyl Copper ................................. References ........................................................
319 320 336 341 348 354 357 359 361 363 381 383 387 387 389
I. Introduction
Well over a hundred bisbenzylisoquinoline alkaloids are presently known. The two benzylisoquinoline units may be bonded together by one, two, or three diaryl ether linkages. When only one diaryl linkage is present, this bond is involved in tail-to-tail or head-to-tail coupling and never in head-to-head coupling. When linked by two or three diaryl ether linkages, the two benzylisoquinoline units can be bonded either head-to-head or head-to-tail. The resultant diversity in the structures of the bisbenzylisoquinoline alkaloids, coupled with their known or
320
MAURICE SHAMMA A N D VASSIL ST. GEORGIEV
potential pharmacological activity, has stimulated substantial interest in their synthesis. This chapter will deal with the preparation of bisbenzylisoquinolines in the order of their structural complexity. Although several interesting and reliable syntheses of bisbenzylisoquinolines have been worked out, e.g., those of ( )-cepharanthine, ( +)-isotetrandrine and related bases, ( + )-0-methylthalicberine, ( k )N-methyldihydromenisarine, ( k )-0-methyltiliacorine, and ( k )-cycleanine, no reliable synthesis of the pharmacologically important ( )-tubocurarine as yet exists. Furthermore, the complexity of the synthetic problem is such that the successful syntheses referred t o above are invariably long and must involve the judicious use of several functional protective groups. Biogenetic-type syntheses using phenolic oxidative coupling of monomeric benzylisoquinolines have unfortunately proven of limited value due sometimes to low yields, but more importantly because it is head-to-head coupling that occurs most readily in vitro, a mode of coupling not encountered in nature. A novel approach to bisbenzylisoquinoline synthesis concerns the electrolytic oxidation of the salts of monomeric phenolic benzylisoquinolines, but so far only one such example has been reported. The most promising new route to the bisbenzylisoquinolines involves the use ofpentafluorophenyl copper in the formation of the diary1 linkage and this method will be discussed toward the end of this chapter.
11. Dauricine-Type Alkaloids

The first attempt a t the synthesis of a dauricine degradation product was carried out a number of years ago when dauricine methyl methine (2) was prepared and was found to be identical with material derived from naturally occurring ( - )-dauricine (3),Scheme 1 ( 1 ) . The sequence in Scheme 1 represents one of the early pioneering efforts in the bisbenzylisoquinoline series. The use of the Erlenmeyer azlactone synthesis in the preparation of the dicarboxylic acid 1 should be noted. Several syntheses of enantiomeric and diastereomeric mixtures of dauricines ( 5 ) are available. The first synthesis was accomplished through the Ullmann -+ Arndt-Eistert +Bischler-Napieralski sequence (Scheme 2). It was not possible to separate the components of the final mixture (2-5). The second synthesis is a variation of the one described above (4-6). Condensation of the diacid chloride of 6 with homoveratrylamine gave the required diamide 4.
6
\
8
0,
$
0 0
Q
3
/ \
5,
Q
0
X
-t
322
K
N
8
m
6.
323
In the third instance, Ullmann condensation of the racemic bromotetrahydrobenzylisoquinoline 7 with racemic armepavine (8) yielded, following hydrolysis, a mixture of dauricines (4-6).
R = benzyl or scetyl
The first synthesis of a clean optically active derivative of dauricine identical with involves the preparation of ( - )-O-methyldauricine (ll), material derived from the natural product (7). Controlled bromination of ( - )-armepavine yielded ( - )-3'-bromoarmepavine (9). O-Methylation then furnished 10, which was condensed under Ullmann conditions with ( - )-armepavine to supply 11, Scheme 3. Several other syntheses of O-methyldauricine are also available. The first of these follows the now well established route involving initial synthesis of the diacid chloride of 1 and its further condensation with homoveratrylamine. The ultimate product was again a product with mixed stereochemical landscape-an enantiomeric-diastereomerk mixture (8). A more arresting approach t o O-methyldauricine was carried out primarily t o prove the usefulness of Reissert intermediates (9). ( _+ )-Armepavine was first prepared in high yield through a Reissert sequence as indicated in Scheme 4. The other required moiety, ( f )-lo, was generated by either of the two routes described in Scheme 5. A related approach t o O-methyldauricine involves a rare instance of bis-Reissert reaction. The dialdehyde 13 was first prepared and then condensed with 2 moles of 12 to yield the dibenzoate 14. The corresponding diol (15) was hydrogenolyzed with hydrogen bromide and zinc in acetic acid to the bisbenzylisoquinoline 16. N-Methylation and reduction then furnished a mixture of O-methyldauricines (9). The
324
D X 0,
2
0
fjp
6.
325
I y=0
326
MAURICE SHAMMA AND VASSIL ST. GEORGIEV
CH30
CH,O CH30 Q N , c , P h
CN
12
3-Rromoanisphenyi lithium, aldehyde, - 40C
CH30$ Br 0--CPh
II
CH30
CH30 Br
3 cH
CH30
I/
ethanol, water 2. z n . nnr
1. KOH,
2. 1. CHJ NaBH,
CH3O Br
CH3
CH30 \
or
CH3O
\
( k 1-10
% NaH,
CH30
0
CH30 Br@
NaBH4
CH,O
Br
1. Zn, HBr 2. CH.1 3. NaBH+
(+)-lo
CH30
SCHEME 5
yields were unusually high throughout this sequence and represent a distinct improvement over the previous syntheses. Yet another synthesis of an 0-methyldauricine mixture utilizing Reissert intermediates proceeded via the condensation of 2 moles of the anion of 12 with the diphenyl ether 17. Basic hydrolysis then yielded the bisbenzylisoquinoline 16 ( 9 ) .The use of Reissert compounds in the synthesis of bisbenzylisoquinolines has been recently further extended
(94.
6.
SYNTHESES OF BISBENZYLISOQUINOLINE
oHc>
ALKALOIDS
327
OCH,
13
R * o < R
\
14 15 16
OCH, R=Ph-COO R=OH R = H
17
A synthesis of ( - )-0-methyldauricine (11) was achieved as a result of preparative work in the berbamunine series. Ullmann condensation of (-)-18 with (-)-armepavine yielded the dimer 19 which upon acid hydrolysis, and diazomethane 0-methylation supplied ( - )-0-methyldauricine (11) (10).
Br
328
\
X
6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS
329
330
Sodium in liquid ammonia reduction of the synthetic dimer 20, a diastereomeric racemate prepared as indicated, afforded diamines 21 and 22. Compound 21 corresponds t o a mixture of dauricines, while 22 is a mixture of deoxydauricines, Scheme 6 (11).An alternate synthesis of 22 is also available through Ullmann condensation of ( k )-23 with (k)-24 (12). The latest and most efficient synthesis of ( f )-0-
OH 23
24
methyldauricine follows the classical lines outlined in Scheme 7 above. The final product was a mixture of diastereomers from which ( & )-0-methyldauricine could be separated (13). The diary1 ether 25, obtained through an Ullmann sequence, was condensed with two moles of 3-methoxy-4-benzyloxyphenethylamine. The product was the diamide 26, which was converted stepwise into a mixture of 0-methyl-0,O-dibenzylmagnolamine (27), Scheme 8 ( 1 4 ) . The dimeric immonium hydrochloride 28 had previously been obtained by a similar sequence (15).
C10 H
OCHaPh
PhCHaO
H C10
28
A first attempt t o synthesize magnoline followed the course outlined in Scheme 9 but aborted when dimer 29 failed to debenzylate (16). A modified route was then adopted which eventually provided a mixture of magnolines (30), Scheme 10 (16).
OCH, 0 c 1 GCHS
>
4 OCH,
25
/p
C H a C \C
26
3. HCOH,
1. pciJ 3. H,, Pt
HCOOH
27
SCHEME 8
332
&
I. 9061. 2. Ethyl chloroformate
'
O\\ ,C-CH, c1
OH
No
\C1
3-Methoxy-4benzyloxy. phenethylamine
OCH,
CH,O
pN\ Fo
1. POCI. 3. 2. CH.1 NaRH,
4. E O H , ethanol
SCHEME 9
6.
0
333
CHz--6, C1 OCOOC,H,
//
0
3-Methoxy-4-hydroxyphenethylamine
f
c 1
m 1 r 3 cH30
1. Ethyl chloroformate 2. 3. CHDI POCla
&
5. 4. NaOH, NaBH, ethanol
OCOOCzH5
H3C
30
SCHEME 10
31
31
33
SCHEME 11
334
The alternate pathway to a bisbenzylisoquinoline,namely, condensation of two tetrahydrobenzylisoquinoline units by means of an Ullmann reaction, was also tried and provided a mixture of magnolines (30) (17). The same sequence was then applied using optically active intermediates. Thus, ( + )-31was condensed with ( -)-32. ( - )-Magnoline(33) was generated following hydrolysis of the benzyloxy protective groups, Scheme 11 (18). It should be noted here that (-)-magnoline (33)is enantiomeric with ( + )-berbamunine. I n related work, ( 5 )-34 was condensed with ( _+ )-35to give rise to a mixture of daurinolines 36, Scheme I 2 (19).Daurinoline itself has the ( - ,- ) or (R, R ) configuration.
34
35
36
SCHEME 12
The alkaloid ( - )-cuspidaline is represented by expression 37,and a synthesis of ( f )-cuspidaline was carried out through a bis-BischlerNapieralski reaction. Following reduction, h7-methylation, and catalytic debenzylation, it was possible to separate the diastereomeric mixture of ( 5 )-cuspidaline by fractional crystallization, Scheme 13 (20). ( & )-4-O-Methylberbamunine (38) has also been obtained by essentially the same route (20).An alternate but closely related preparation of a mixture of cuspidalines is also available using the intermediate 39 (21).
6. SYNTHESES
OF BISBENZYLISOQUINOLINE ALKALOIDS
335
COOH
3-Methox y-4-benzyloxy-
CHaCOOH
phcnethylamine. decalin, A
H3C
Fractional crystallization
_____j
SCHEM E
13
336
39
111. Magnolamine-Type Alkaloids

The structure of magnolamine (42) was first confirmed by the synthesis of the optically active tetra-0-methylmagnolamine (4l), enantiomeric with naturally derived ( + )-tetra-0-methylmagnolamine (43). Ullmann condensation of ( - )-6-bromolaudanosine (40) with ( - )armepavine gave a small yield of 41 whose physical properties compared favorably with those of 43 (22). Likewise, a diastereomeric tetra-0methylmagnolamine was obtained by the Ullmann condensation of ( - )-6-bromolaudanosine with ( + )-armepavine (23). A synthesis of a stereoisomeric mixture of magnolamines has been reported, but it was not possible to separate the components of this mixture (24, 25). This synthesis, which relies upon early formation of the diphenyl ether linkage, is outlined in Scheme 14.Noteworthy in this synthetic sequence are the hydrolysis of the methylenedioxy group, the further protection of the o-diphenol as the dibenzyl ether, and the bisBischler-Napieralski cyclization leading to the required skeleton of magnolamine. I n point of fact, a bis-Bischler-Napieralski cyclization had been carried out earlier in the magnolamine series when the diacid 44,obtained by either of the two routes indicated in Scheme 15, had been converted to the analog 45 of magnolamine (26). A mixture of enantiomeric and diastereomeric magnolamines has
6.
337
0CH3
40
OCH,
41
and
OH
42
CH300C
COOCH,
PhCH2CI, NaOH, CHBOH
OH c H
ca ~ C
1. Basic SOCl,,hydrolysis pyridine 3 2.
3. CAaN2
t
OCH,Ph OCH,Ph
3-Methoxy-4-benzyloxyphenethylamine, silver benzoate, N(C2Hda
( Arndt-Eistert)
OCH,Ph
1. POC13 2. C H ~ I 3. NaRH, 4. Conc. HCI, ethanol
OCHaPh
H3C
CH3
OH
Mixture of enantiomeric and diastereomeric m a g n o l a m i n e s SCHEME 14
OCH,
c
OCH,
KCN, acetone ethanol,
&
OCH, CHa-CN
OCH, HOOCCH,
poa~
\ OCH, I OCH,
44
Hydrolysis
or alternatively,
Br
OCH,
C H 3 0 0 C - H ~ C ~ o ~ C H 2 C O O C Hydrolysis H 3 44
\
then,
S0Cl2
OCH,
OCH,
1. 3-Methoxy-4-benzyloxyphenethylamine 2. PC15, CHCI. (Bischler-Napieralski)
9
44
Diacid chloride
OCH,
45
SCHEME 16
340
M A U R I C E SHAMMA A N D VASSIL ST. GEORGIEV
also been prepared through Ullmann condensation of two tetrahydrobenzylisoquinoline units. This sequence, which uses both benzyloxy and ethoxycarbonyloxy protective groups, is shown in Scheme 16 ( 2 7 ) .The simple analog 46 of magnolamine has also been prepared through the Ullmann condensation of two tetrahydrobenzylisoquinoline units and was obtained as an isomeric mixture (28).
3H30
PhCH,O
1. POCI., toluene
PhCH,O
2. CH31 3. NaRH,
C,H,OOCO
then,
HO
CH30
PhCH,O
CH3
yl
OCH,Ph
+
HO
1. Ullmann 2. Hydrolysis
OCHzPh
Mixture of enantiomeric and diastereomeric magnolamiries SCHEME 16
o
46
6.
341
IV. Berbamine-Oxyacanthe-Type Alkaloids

Initial efforts in this series provided preparations of such intermediates as 47 to 50 (29-34). The first synthesis of ( + )-tetrandrine (54) was achieved in low yield by Ullmann condensation of ( + )-N-methylcoclaurine (53)with ( - )-3,8-dibromo-N,O,O-trimethylcoclaurine (51)
48
HOOC
COOH
49
50
obtained by bromination of 53 followed by 0-methylation. 0 , O Dimethylbebeerine (55) should have been a by-product of this condensation but was not actually isolated and characterized, Scheme 17
(35).
An interesting total synthesis of optically active natural ( )isotetrandrine (65) ( - )-phaeanthine (66),and ( + )-tetrandrine (54) has been achieved (36, 37). The first required intermediate, ( - )-0-benzyl-8bromolaudanidine (56), was prepared through exploitation of a Willgerodt reaction as shown in Scheme 18.
342
rtl. K I .
K~(:o~.
pyridinr. A
SCHEME 17
Another intermediate was N-tert-butoxycarbonyl-4-hydroxy-3methoxyphenethylamine (57) and the preparation of this urethan is given in Scheme 19. The tert-butoxycarbonyl group is removable by acid but is resistant to hydrogenolysis and base hydrolysis under relatively mild conditions. Ullmann condensation of 56 with 57 furnished the diary1 ether 58 in good yield. Catalytic debenzylation was followed by
55
6.
CHa
SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS
343
I c=o
9, morpholine, A
CF,--CN
ll
A0
NaOH
OCHIPh OCH3
OCH,Ph OCH,
1. POCl3 2. NaBR, 3. Resolution via
I (+ )-tartaric acid salts 4. HCOH. NaBH,
OCH,Ph OCH,
H3C H-
a:-;
Br
56
H z .
SCHEME 18
another Ullmann condensa-ion with the -bird required intermediate, namely, methyl p-bromophenylacetate, to supply the bisdiaryl ether 59, again in good yield, Scheme 20. When the bisdiaryl ether 60 was heated, the amide 61 was produced, which generated the key imine 62 upon Bischler-Napieralski cyclization.
tcrt-Rutyl aaidoformate, N(CzH,)3, cthyl acetate
PhCH,O c H 3\ 0 p N H z
PhCH,O 0- tert-butyl
HO
0-&t-butyl
57
56
+ 57
CUO. KzCOa, pyridine, A
1. Hz, Pd/C, PdClz (debenzylation) 2. Methyl p-bromophenylacetate, CuO, K2C03, pyridine, A
58
1. OH@, then H 3 0 @
(hydrolysis)
/N
/
O--t&-butyl
2. p-Nitrophenol, DCC
fo
(ester formation) 3. CF,COOH (removal Of tcrt-butoxyrarbon yl)
59
SCHEME 20
6.
345
60
DMF, pyridine, A
POCI3, CHC13
A
61
The reduction of imine 62 was studied under a variety of experimental conditions. With sodium borohydride in methanol, a 3 : 2 ratio of bisbenzylisoquinolines 63 and 64 was obtained, which were N-methylated t o ( + )-isotetrandrine (65) and ( - )-phaeanthine (66), respectively. But when zinc in sulfuric acid was utilized on the racemate of 62, only 64, as the racemate, could be isolated. No stereospecificity in the reduction of 62 was observed with Adains catalyst containing a trace of concentrated hydrochloric acid. AT-Methylationof racemic 64 gave a racemic compound composed of ( - )-phaeanthine (66) and its enantiomer (+)-tetrandrine (54), Scheme 21 (37).Since ( )-66has been isolated from a natural source and resolved into its optical antipodes (37a), the present synthesis amounts also t o a total synthesis of ( + )-tetrandrine. The first successful syntbssis of ( i )-cepharanthine (73), belonging to the oxyacanthine series, w5Fachieved through the Bischler-Napieralski cyclization of the key bislGtam 72. One precursor of this important intermediate was the substituted aminourethan 69, which was prepared from species 67 and 68 as shown in Schemes 22 and 23 ( 3 8 , 3 9 ) . The lower half of cepharanthine was prepared as in Scheme 24, taking advantage of the fact that a benzyloxy group can be hydrogenolyzed while a tert-butyl ester is immune. Condensation of 69 w i t h 9 0 furnished the urethan 71, which was converted to the bislactam 32. Bischler-Napieralski cyclization gave a bisimine, which could be rexuced to a bis secondary amine either with
346
x
0
s + i!
W
x
0
.%&
;&
0 , O
0
I W n
z x
u,
X
6.
ALKALOIDS
347
Br
Br
67
SCHEME 22
Adams catalyst or with sodium borohydride. Since the ratios of the two diastereomers obtained from each of these reductions were different, the available mixtures of secondary amines were combined, Nmethylated, and then separated by chromatography. One of the products isolated proved t o be ( & )-cepharanthine (73), Scheme 25 (38'39). It was found possible t o convert the unusual bisbenzylisoquinoline alkaloid stepinonine (74) to N,O-dimethyltetrahydrostepinonine(75), which in turn could be selectively oxidized with Jones' reagent to the
1. Ethyl chloroformate, pyridine 2. Zn/Hn, HCI
rNo1
Ph-CH,
-0-
H0
\
CI
HO
C,H,OCO
0
CH30 HO 0
then,
1. CuO, K1C03. pyridine, A
It
OCHpPh
68
OCHIPh
67
+ 68
2. Dil. HCI (formyl hydrolysis)
OCH,Ph
69
SCHEME 23
348
COOH
COO-tert-Bu
ter2-Butyl alcohol, POC13, pyridine
H a , PdtC
OCHSPh COO- tert-Bu

~OOCH.
bOCH2?h
p-Toluen esulfonic acid (removal of CU,A ( ~ l ~ r n a n n )
tcrl-Bu group)
70
SCHEXE 24
ketone 76. R e d u c h n of this ketone first with zinc in acetic acid and then with sodium borohydride yielded a mixture of O-methylrepandine (77) and O-methyloxyacanthine (78) (39a). A mixture of enantiomeric and diastereomeric berbamines (82) and oxyacanthines (83) was obtained through the following sequence. Schotten-Baumann reaction of the diamine 47 with the diacid chloride 79 gave amides 80 and 81, which could be separated. Bischler-Napieralski cyclization using phosphorus oxychloride produced the corresponding 3,4-dihydroisoquinolines. N-Alkylation with methyliodide, borohydride reduction, and subsequent acid hydrolysis generated isomeric mixtures of berbamine 82 and oxyacanthine 83, respectively (39b).
V. Thalicberine-Type Alkaloids
( + )-Thalicberine (84) and ( +)-O-methylthalicberine (85) are representative of a group of bisbenzylisoquinoline alkaloids found in Thalictrum species (Ranunculaceae), and a synthesis of ( + )-O-methylthalicberine has been reported (40, 41). Ullmann condensation of ( + )-O-benzyl-8-bromolaudanidine (86) with the phenolic tert-butylurethan 87 afforded the diary1 ether 88, which was then hydrogenolyzed t o the phenol 89, Scheme 26.
CH,O'
HN
2. H., Pt or NaRHI
1. POClD
\
H3C
3. HCOH.NaBH, 4. Chromatography
79.
78
SCHEME 25
6. SYNTHESES OF
BISEENZYLISOQUINOLINE ALKALOIDS
351
352
84 85
R = H R = CH,
CuO, K,CO.,
+
0-tert-Bu
OCHaPh
86
87
0- tert-Bu
OCH,Ph
88
0 -tert-Bu
OH
89
SCHEME 26
6.
m
Y)
353
LI
354
Phenol 89 was condensed in a second Ullmann condensation with methyl-p-bromophenylacetate to yield the ether 90, which was converted to the amide 91 by the p-nitrophenyl ester method. BischlerNapieralski cyclization then gave the imine 92. Reduction of this imine with sodium borohydride gave only a single compound, namely, the desired amine 93. N-Methylation furnished the final product, ( + )-O-methylthalicberine (85)) identical with the natural material, Scheme 27.
VI. Trilobine-Isotrilobine-Type Alkaloids

The alkaloids ( + )-trilobine (94) and ( + )-isotrilobine (95) possess a diphenylenedioxy bridge connecting the two top aromatic rings. It has been possible to interrelate chemically bases of the berbamineoxyacanthine group, which contain two diary1 ether linkages, to those belonging to the trilobine-isotrilobine series, and these interrelationships will be discussed briefly here. When naturally occurring ( )-isotetrandrine (65) was heated with hydrobromic acid a t lOO"C, the demethyl derivative 96 was obtained. This derivative cyclized to the trilobine-type compound 97 upon more drastic treatment with hydrobromic acid, and diazomethane O-methylation yielded the methyl ether 98, Scheme 28 (42).
94 95
R = H R = CH,
I n a similar vein, ( + )-tetrandrine (54)) which is diastereoisomeric with ( + )-isotetrandrine (65), was converted to the diphenylenedioxy derivative 99 (43). The starting alkaloids in the two examples above belong to the berbamine series, but diphenylenedioxy formation can also be brought about in the oxyacanthine series. Thus, oxyecanthine (100) itself was converted into the derivative 101 (44) while N-methyldihydroepistephanine (102)led to the levorotatory antipode 103 of natural
6.
355
H3C
CH3
HBr, 100C,3 hours
65
H3C a>? /N 'H &
HBr. 130-135C, 3 hours
/
\
OH
96
0 \
97
98
R = H R = CH3
SCHEME 28
54
356
6.
ALKALOIDS
357
104
1. HBr, HOAc, 100C
2. HBr, 140-145C
t 3. CHaNa
(+-1-95
SCHEME 29
( + )-isotrilobine (45).Finally, taking advantage of the known fact that in dilute acid ( + )-oxyacanthine (100) undergoes isomerization to ( - )-repandine (104),it was found possible to convert ( + )-oxyacanthine into natural ( + )-isotrilobine, Scheme 29 (46). Inubushi and co-workers have recently adapted their synthesis of ( + )-isotetrandrine and ( - )-phaeanthine to preparations of ( + )obaberine and ( -t)-trilobine (46a).
VII. Menisarine-Type Alkaloids

The alkaloid ( + )-menisarine possesses the structure 105, which incorporates a diphenylenedioxy bridge, and an interesting synthesis of ( )-N-methyldihydromenisarine (107) has been achieved. The first stage of the synthesis concerned the preparation of the diamine 106, which was carried out via a double Ullmann, as shown in Scheme 30 (47, 48). The lower half (1) of the molecule was prepared using a Willgerodt reaction as per Scheme 31.
105
358
MAURICE SRAMMA AND VASSIL ST. OEORGIEV
cu, pyridine.
A
t
Br
OCH,
OH
OH
OCH,
OCH,
106
SCHEME 30
Condensation of the diacid chloride of 1 with the diamide 106 a t high dilution, followed by Bischler-Napieralski ring closure, reduction, and Eschweiler-Clarke N-methylation furnished the desired racemic product 107, Scheme 32 (47, as), which was spectrally identical with the product derived from the reduction and N-methylation of natural ( + )-menisarine (105).
don
0
1. CH&OCI, AICI., 2. Dlmethyl G S . sulfate
II
'
HWillgerodt 3
6.
108
359
+ Diacid chloride of 1
2. NaBH,
107
SCHEME 32
VIII. Tiliacorine-Type Alkaloids

( + )-Tiliacorine and its diastereomer ( + )-tiliacorinine have been assigned structure 108 on the basis of extensive degradative studies ( 4 t h ) .These two alkaloids are unusual in having a biphenyl system in lieu of the usual diary1 linkage. A total synthesis of ( k )-O-methyltiliacorine (109) has been described in detail (49). Unsymmetrical Ullmann condensation of the bromophenols 110 and 111 yielded a mixture of three products from which the desired diester 112 was isolated by chromatography. Homologation and conversion to the diamine 113 was followed by condensation with the diacid chloride 114. The resulting bisamide 115 was converted to a mixture of ( f )-0methyltiliacorine and O-methyltiliacorinine by well established transformations. Careful chromatography of this mixture yielded ( f )-0methyltiliacorine, spectroscopically and chromatographically identical with material derived from the alkaloid. The diastereoisomeric ( f )-0methyltiliacorinine was obtained only in trace amounts, Scheme 33 (49).
360
MAIJRICE SHAMMA A N D VASSIL ST. GEORGIEV

1. K salts formation
C H 3 O O C ~ O C H a
~
B r D 2. 3. c Cu-bran=, Chromatography 0 diphenyl 0 ether, c A H
'
Br
110
OH
HO
111
vD C O O C H ,
o\
112
1. LiAlH, 2. 3. S0Clz KCN

4. H.,
NYR)
113
then,
113
COCl
__f
114
115
6.
ALKALOIDS
361
1. CHJ 2. NaBH, 3. POC1.

4. H2, Pt
5. HCOH, HCOOH
108 R = H 109 R = CH,
SCHEME 33
IX. Liensinine-Type Alkaloids

The alkaloid ( + )-liensinine (118) incorporates head-to-tail coupling through a diary1 ether linkage. A total synthesis of this alkaloid was achieved on the heels of the initial isolation and characterization reports. Ullmann condensation of ( - )-116 with ( - )-117 followed by hydrolysis gave the optically active alkaloid (50, 51). A synthesis of a diastereomeric mixture of liensinines, by a somewhat similar pathway, is also available ( 5 2 ) . The related alkaloid ( - )-isoliensinine (122)yields ( - )-O,O-dimethylisoliensinine (121)on treatment with diazomethane. Derivative 121 was synthesized by Ullmann condensation of ( - )-119 with ( - )-120 (53). Finally, optically active ( - )-isoliensinine (122) was obtained by the sequence in Eq. 1 ( 5 4 ) .Worthy of attention are the new conditions for the Ullmann condensation ( 5 2 , 5 4 )involving the use of copper powder, potassium carbonate, a small amount of potassium iodide, and dry pyridine heated to 155-160'c in a current of nitrogen. These conditions give better yields (about 15y0)than the usual Ullmann condensation. The newer base ( - )-neferine (123), related t o liensinine and isolienshine, was synthesized by a similar approach (Eq. 2 ) (55).
CH,O
HO
Y~cH,\ /
I I Br I / I Y \ C H 3
1. Ullmann 2. H,OB
PhCH,O
\
116
PhCH,O
117
cH30m
CH, O b \ F O O H
Hac,5:>:
I
OCH,
119 120
6.
363
CH,O
PhCH,O
\CH,
CH30
LY
CuO, K.COa. pyridine, A
HO
CH30
0 R
CH,
1 OCH,
OCH,
123
X. Curine-Chondocurine-Type Alkaloids
It was conclusively demonstrated in 1970 that the hitherto accepted structure for the alkaloid ( + )-tubocurarine,which had been represented as 124, was in error and that the correct structure is 125 (56, 57). This finding was of particular interest not only because of the importance of ( )-tubocurarine as a neuromuscular blocking agent, but also because of the fact that supposed total syntheses of the racemic di-0-methyl ether of tubocurarine iodide as well as of racemic tubocurarine iodide
364
X0
H
I
m
\
,H
$4
125
124
had been claimed previously. A description of the synthetic work on tubocurarine follows. This description is complicated not only because of the above mentioned change in structural assignment, but also by the failure of the workers involved in the synthetic work in clearly differentiating between enantiomers, racemates, and diastereomers while comparing samples (58-62). As a preliminary attempt at the synthesis of the dimethyl ether of tubocurarine, the simple dimer 126 was constructed as described in Scheme 34. The product 126 was obtained as a mixture of two diastereomers from which the predominant racemate (mp 96-99C) could be isolated (58). Essentially the same approach was utilized in the preparation of the so-called di-0-methyl ether of tubocurarine iodide ) (127), Scheme 35 (58, 59). The UV spectrum of one salt so obtained was apparently close t o or identical with the spectrum of an authentic sample of the di-0methyl ether of ( + )-tubocurarine iodide, and this finding was taken as proof of structure.* It must be pointed out, however, that most tetrahydrobenzylisoquinolines, as well as bisbenzylisoquinolines such as tubocurarine or its dimethyl ether, exhibit a maximum absorption near 280 nm, so that UV spectroscopy is not a reliable basis for comparison. Another criterion used was a mixture melting point between the
* There seems to be some confusion in the assignments of melting points of the final products. I n reference ( 5 8 ) , two supposed diastereomeric tubocurarine iodides were obtained (mp 131-135C and 223-228C). But in reference ( 5 9 ) , only one melting point was quoted [mp 257-268C (ethanol)]. This latter material apparently gave no melting point depression with a sample of the natural salt (mp 262-264C), even though no formal resolution was carried out on the synthetic material.
6.
365
CH,O
CH,O C
3 '
H , O P
N,
" r
3
PhCH,O
HO
___,
CH,O CH30\/ CH,O
'
CH3 C H 3 0
'
(636 ..jCx; 5' 6

G N \ C H , N\CH3
1.
Homoveratrylaminr
I. H , , Pt 2. HC'OH, HCOOH
2. PO('I3
\
CH, COOCH,
/
OCH, CH, OCH3
OCH,
SCHEME 34
cH30)3? Jy '
FOOH
HO
NHa
PhCH,O
PhCH,O
L y
2. 209. HCI, A, 2 hours
Cu, KOH, pyridine, 16O-18O0C
OCH,Ph
OCH, OCH,
1. Zn, dil. HOAc, A, 1.5 hours 2. CHJ.CH30H
I" H 3 c \ : f 0 C H 3
H,C/ OCH,
127
OCH, SCHEME 35
368
6.
369
a 0, m
m c
6.
ALKALOIDS
371
naturally derived dextrarotatory di-0-methyl ether of tubocurarine iodide and the synthetic isomer, in which apparently no depression was observed. Such a comparison is, of course, invalid since (a) a racemate usually has a different melting point from that of a pure enantiomer, (b) melting points of bisbenzylisoquinoline salts are often unreliable and difficult t o reproduce, and (c) the structure assigned to ( + )-tubocurarine and its di-0-methyl ether was in error in the first place. A synthesis of the unsubstituted tubocurarine analog 129 is also known, Scheme 36 (63). The product proved t o be a mixture of two racemates, mp 225227C and 121-124C. As an extension of the synthetic work on the so-called di-0-methyl ether of tubocurarine, a preparation of the di-0-methyl ether of racemic chondodendrine (130) was carried out, Scheme 37 (64). A slightly different approach t o the so-called di-0-methyl ether of tubocurarine has also been recorded, Scheme 38 (60). The starting material was the diimine 131, which was known from previous work. Each of the two diastereomeric racemates of 132 gave two bismethiodides upon treatment with methyl iodide, a result that is somewhat difficult to rationalize; and one of these four isomeric salts, namely, that melting 257.5-259c, was claimed to be identical with the dextrorotatory di-0-methyl ether iodide of natural ( + )-tubocurarine iodide. The criteria for comparison were simply closeness of UV spectra and melting points. A claim of a synthesis of a material assumed t o be identical with natural ( + )-tubocurarine iodide was put forward, even though an actual
1. Cu, K,COa,
2. Zn, HOAc
CH,
% Bismethiodide
salts
131
133
SCHEME 38
372
CH30 K@ 0
, Cu, A
OCHaPh CH,O
0
A
----.-+
Ac.0, pyridine
OCHaPh
CHa
OCHaPh
I COOCH, CHa
&:H
133
OCH,
C H d , NaOH, CH30H, A
OCH,
HNdo HN
Br
OCH,Ph
CH,
OCH,Ph
OCH,
OCH,
184
135
6.
then,
ALKALOIDS
373
IQ
134
H H,C' 3
H ~
OCH,
IQ
136
SCHEME 39
separation of optical isomers had not been carried out. This synthesis is further obscured by the fact that two phenols corresponding t o structure 133were asserted t o exist, as well as two of the acetates 134 and two of the diamides 135.The final salt 136 was obtained as two compounds, one melting 257-260.5"C and the other 210-212C. The former salt was claimed to be identical with (+)-tubocurarine iodide on the basis of UV spectral comparisons and identity of melting points ( !), Scheme 39 (61),even though no separation of enantiomers was performed.
1. A c p O 2. P0Cl3, C H C L A 3. H30@ 4. Cu, K.C03, pyridine, 150-1 80C 5. Zn , AOAc
$ H 2
OCH,Ph
H N & O H
H N & o H
/
OCH,
SCHEME 40
137
OCH,
374
Finally, a synthesis of racemic so-called N , N -demethylchondodendrine (137)) erroneously assumed by the authors t o be identical with chondrofoline, has also been advanced and is described in Scheme 40 (62).Two products were obtained a t the conclusion of the sequence, and one of them was assumed to correspond t o chondrofoline on the basis of UV spectral comparisons and a negative Millon test. It was later shown by other workers that the correct structure for chondrofoline is 138 (65)) so that the claim of a synthesis of chondrofoline is unfounded (62).
((
: 0~
OCH,
138
I n other attempts a t the synthesis of tubocurarine-type bases, Ullmann condensation of the dibromotetrahydrobenzylisoquinoline 139 with the N-methylcoclaurine salt 140 was investigated but did not lead t o characterizable product (66).Studies of the efficient Ullmann condensation of phenols with aromatic halides substituted a t the ortho position(s)with nitro group(s)have been carried out and have culminated in the preparation of the imide 141 (67-69). 0,O-Dimethylcurine (143) was presumably obtained in the course of the previously described syntheses. But a more reliable preparation of this compound involves the Ullmann condensation between the levorotatory dibromotetrahydrobenzylisoquinoline 139 and the levorotatory diphenolic tetrahydrobenzylisoquinoline 142 (70). When the catalyst for the condensation consisted of cuprous chloride in the presence of potassium carbonate and pyridine and the conditions were heating a t 155-165C for 24 hours, a small yield of optically active 0,O-dimethylcurine (143) together with a larger amount of 144 was obtained. When, however, the two starting tetrahydrobenzylisoquinolines were racemic rather than levorotatory and the catalyst was cupric oxide in pyridine
6.
375
141
heated a t 160-170C for 50 hours, the products consisted of a small yield of a mixture of 0,O-dimethylcurines together with a mixture of tetrandrines and isotetrandrines (54), as well as a mixture of 144. Ullmann condensation of 2 moles of the racemic phenolic tetrahydrobenzylisoquinoline 145 followed by N-methylation yielded the hayatine analog 146 (2'1). Turning now to the structurally simpler alkaloid ( - )-cycleanbe (147), a promising route to its preparation appeared to be Ullmann condensation of 2 moles of 8-bromoarmepavine, since the alkaloid is symmetrical.
376
1. Cu, aq. NaOH, A 2. C H J
c 1
145
OCH,
'o
OCH3
146
One such attempt using ( k )-8-bromoarmepavine (148) and the superior cupric oxide-potassium carbonate-pyridine catalyst gave some of the dimer 149 but none of the expected mixture of cycleanines (72). A fully authenticated first total synthesis of ( k )-cycleanine (147) involved as a first hurdle the synthesis of the amino acid 151 as well as that of its corresponding methyl ester 155 (73, 7 4 ) . The aldehyde 150 was condensed with nitromethane to give a yellow nitrostyrene. Catalytic hydrogenation over Adams catalyst in acetic acid then gave the required amino acid 151, Scheme 41. Furthermore, the methyl ester 155 of the acid 151 was synthesized by the following alternate route. 3,4-Dimethoxy-5-bromophenethylamine, prepared by the reduction of the nitrostyrene 152 under Clemmensen
CH,O
CH30
:\CH3
::::q cH30
Br
+I$
H 3 c \ : M 0 C H 3 OCH,
147
6 44
CH, CH,O OH CH, OCH,
I49
CH3
148
cH30vcH 4 *(I
CH30
1. CH3NOa
6.
ALKALOIDS
377
" CH30 " " T N H ,
2. Ha, Pt, HOAc
CH,COOH
CH,COOH
150
151
SCHEME 41
conditions, was converted to the N-carbobenzoxy derivative 153. Ullmann condensation between 153 and methyl p-hydroxyphenylacetate afforded the product 154, and catalytic removal of the blocking group gave rise to the desired methyl ester 155, Scheme 42. The amino acid 151 was next protected as its N-carbobenzoxy derivative 156. Condensation between 155 and 156 furnished the amide
1. Zn/Hg, HCl
c H 3 0 T v " 0 2
2. Ph-CHP-O-C
' 40
c1
CH30
Br
152
CH,O
cH30qT
Br
153
H o ~ c H 2 - - C O O C H I . CuO, K.CO3, pyridine

t
OCH,Ph
CH30
CH&OOCH,
154
CH2COOCHS
155
SCHEME 42
378
MAURICE SHAMMA AND VASSIL ST. OEORGIEV
0, M
=.I;
0
6.
m
379
380
157, which was converted t o the carboxylic acid 158. Esterification of 158 with p-nitrophenol and DCC was followed by treatment with hydro-
gen bromide to remove the carbobenzoxy group. The resulting amine hydrobromide 159 readily suffered cyclization t o the bisamide 160, and Fischler-Napieralski cyclization followed by reduction led to a mixture of tetrahydroisoquinolines. N-Methylation finally furnished a mixture
CH,O
cH30v cH30 44 66
\
Po
CH30
N\CH3
OCH,Ph
OCH,Ph
HN&z s^
3 H c
163
o & .
H. C\ N ) OCH,
164
OCHaPh
H,CLN&
CH, OCH,
165
6.
381
of products which generated ( t )-cycleanhe (147)after chromatography. Two other products obtained from the chromatographic separation were the dimers 161 and 162, Scheme 43. A later study in the cycleanine series demonstrated that BischlerNapieralski cyclization of the amide 163 proceeds in two directions to supply ultimately amines 164 and 165 (75). XI. Miscellaneous Syntheses
The alkaloid aztequine was supposedly isolated from the leaves of yoloxochitl, Tabma mexicana Don. (Magnoliaceae) and was assigned structure 166 with no delineation of stereochemistry. This assignment is certainly in error, since in the same paper the unlikely claim was made that hydroiodic acid ruptured the diaryl ether linkage of the alkaloid without touching the methoxyl groups (?G).
OH
166
OH
Attempted syntheses of 166 either involve initial preparation of the diaryl ether corresponding to the two bottom rings, followed by further elaboration to construct the two tetrahydroisoquinoline units, or include an Ullmann condensation to bond together the two tetrahydrobenzylisoquinoline units (77-79). The bisbenzylisoquinolines 167, 168, and 169, which have no analogs in nature, have been synthesized through Ullmann condensation between 170 and 171 in the case of 167; 172 and 173 in the case of 168; and 174 and 175 in the case of 169 ( 8 0 , S l ) .
167
382
168
169
170 R, = OH, R, = H 171 R1 = Br, R, = H 172 R, = H, Ra = OH 173 R, = H, R, = Br 174 R1 = H, RP = OH 175 R, = Br, R, = H
The dimer 176 has also been prepared in the course of a study of structural requirements for tumor-inhibitory activity among bisbenzylisoquinolines (13).
Lastly, an important related synthesis that should be a t least mentioned here in passing is that of the alkaloid ( + )-thalicarpine (177), which is an aporphine-benzylisoquinoline rather than a bisbenzylisoquinoline (82-84).
6.
383
XU. Syntheses Using Phenolic Oxidative Coupling

Historically, significant attempts a t the phenolic oxidative coupling of tetrahydrobenzylisoquinoline free bases were reported as early as 1932, but they generated only dibenzopyrrocolines (85, 86). The first phenolic oxidative coupling leading to a bisbenzylisoquinoline was not reported until 1962, when it was shown that ferricyanide oxidation of the quaternary salt ( +_ )-magnocurarine iodide (178) at pH 10 yielded the dimer 180 in 1Sy0yield (87, 88).
RO
-0
178 R = H
179
R = CH3
XQ
0 #
RO
OR
x@
R = H 181 R = CH,
180
384
6.
ALKALOIDS
385
Similarly, ( f )-4-O-methylmagnocurarine iodide (179) furnished the corresponding dimer 181, while ( )-armepavine methiodide, which has a methoxy group a t C-7 and a hydroxy a t C-4, could not be dimerized (87-89). I n a variation on this theme, and using the free base instead of the quaternary salt, it was demonstrated that ferricyanide oxidation of ( f )-4-O-methyl-N-methylcoclaurine (182) in a two-phase system of chloroform-0.1 N sodium carbonate (pH 11.4) a t or below room temperature resulted in formation of the racemic diastereomers 183 and 184 in about 15% yield and separable by chromatography, Scheme 44 (901. It will be recalled that in an initial attempt it had been found that ( k )-armepavine methiodide did not dimerize a t room temperature. Reexamination of this oxidation under more severe conditions, namely, 0.1 N sodium carbonate solution and potassium ferricyanide on a steam bath or 1 N sodium hydroxide and silver nitrate a t room temperature, produced the carbon-carbon dimer 185 in about 15y0 yield (91,92).
185
In an atte.mpt to prepare the aporphine base ( f )-N-methylcaaverine (186) by phenolic oxidative coupling, the ferric chloride oxidation of racemic tetrahydrobenzylisoquinoline 187 was investigated. The products were the dienone 188 in 2.4y0 yield and the dimeric benzylisoquinoline 189 in 1.1% yield, Scheme 45 (93). A few studies have also been concerned with the enzymatic oxidation of tetrahydrobenzylisoquinolines. Oxidation of ( 5 )-N-norarmepavine (190) a t pH 6.5 with crude horseradish peroxidase and hydrogen peroxide yielded a complex mixture that included small yields of the isoquinolines 191, 192, and 193, Scheme 46 (94). Other investigations have dealt with the enzymatic oxidation of phenethyltetrahydroisoquinolines (95, 96).
c HO H 3 0 p N \ C H 3
aq. FeCl,, 30:40'C
CH3
+ H3C'
J & K l.
HO
CH3
\
189
'
OH
187
188
186
SCHEME 45
6.
ALKALOIDS
387
HO
J 9
190
cH30p
CH,O
191
HO OH
192 198
OH
SCHEME 46
XIII. Synthesis Using Electrolytic Oxidation The first preparation of a naturally occurring bisbenzylisoquinoline alkaloid, namely, dauricine, using an oxidative method occurred when the sodium salt of ( )-N-carbethoxy-N-norarmepavine (194) was subjected to electrolysis using tetramethylammonium perchlorate as the electrolyte, a graphite anode, and a platinum cathode (97). A mixture of the dimers 195 and 196 was obtained and separated. The dimer 196 then furnished a racemic and diastereomeric mixture of dauricines 3 following 0-benzylyation, reduction, and catalytic debenzylation. Such an electrolytic oxidative dimerization was unsuccessful when the nitrogen function was not protected, Scheme 47.
XIV. Use of Pentafluorophenyl Copper

The most promising avenue to the bisbenzylisoquinolines presently appears to be via an improved Ullmann diary1 ether synthesis utilizing pentafluorophenyl copper in dry pyridine. Thus condensation of
388
CaH5OOC /N
m zElectrolysis in wet
acetonitrile
b
194
e Nee
C2H,00C/N
OCH,
CH,O
195
196
then,
1. 2. PhCH.CI, ImiAIH4 base
H3C
t
N P
H OCH3 3
196
3. H., PdIC
cH3
CH3O
SCEEME 47
6.
389
( + ) - 6'-bromolaudanosine (197)with ( + )-armepavine and pentafluoro-
phenyl copper in dry pyridine gave an impressive 53y0yield of the dimer 198, the S,S isomer of tetra-0-methylmagnolamine (98). Analogous condensations have also led to the preparation of aporphine-benzylisoquinoline dimers (98).
OCH,
198
REFERENCES
H. Kondo, Z. Narita, and S. Ueyo, Ber. 68, 519 (1935). T. Kametani and K. Fukumoto, Pet. Lett. 2771 (1964). T. Kametani and K. Fukumoto, J. Chem. SOC.6141 (1964). K. Fujitani, Y. Aoyagi, and Y. Masaki, Yakuqaku Zasshi 84, 1234 (1964). K . Fujitani, Y. Aoyagi, and Y. Masaki, Yakuqaku Zasshi 86, 654 (1966). T. Kametani, S. Takano, R. Yanase, C. Kibayashi, H. Ida, S. Kano, and K. Sakurai, Chem. Pharm. Bull. 14, 73 (1966). 7. M. Tomita, K. It6, and H. Yamaguchi, Chem. P h a m . Bull. 3, 449 (1955). 8. I. N. Gorbacheva, G. V. Bushbek, L. P. Varnakova, L. M. Shulov, and N. A. Preobrazhenskii, Zh. Obxh. Khim. 27, 2297 (1957). 9. F. D. Popp, H. W. Gibson, and A. C. Noble, J . Orq. Chem. 31, 2296 (1966). 9a. D. C. Smith and F. D. Popp, J . Heterocycl. Chem. 13, 573 (1976). 10. T. Kametani, K. Sakurai, and H. Iida, Yakugaku Zasshi 88, 1163 (1968). 11. K. Fujitani and Y. Masaki, Yakugaku Zasshi 86, 660 (1966).
1. 2. 3. 4. 5. 6.
390
12. M. Tomita and J. Niimi, Yakugaku Zasshi 79, 1019 (1959). 13. S. M. Kupchan and H. W. Altland, J. Med. Chem. 16, 913 (1973). 14. I. N. Gorbacheva, L. P. Varnakova, E. M. Kleiner, I. I. Chernova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 28, 167 (1957). 15. I. N. Gorbacheva, E. N. Tzvetkov, L. P. Varnakova, A. I. Gavrilova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 25, 1423 (1955). 16. T. Kametani, R. Yanase, S. Kano, and K. Sakurai, J. Heterocycl. Chem. 3,239 (1966). 17. T. Kametani, H. Iida, and K. Sakurai, Chem. Pharm. Bull. 16, 1623 (1968). C 500 (1969). 18. T. Kametani, H. Iida, and K. Sakurai, J. Chem. SOC. 19. T. Kametani, S. Takano, T. Kobari, H. Iida, and M. Shinbo, Chem. Pharm. Bull. 16, 1625 (1968). 20. M. Tomita, K. Fujitani, Y. Masaki, and Y. Okamoto, Chem. Pharm. Bull. 16, 70 (1968). 21. T. Kametani and F. Satoh, Chem. Pharm. Bull. 16, 773 (1968). 22. M. Tomita and K. It6, Yakugaku Zasshi 78, 103 (1958). 23. M. Tomita and K. It6, Yakugaku Zasshi 78, 605 (1958). 24. T. Kametani and H. Yagi, Tet. Lett. 953 (1965). 25. T. Kametani and H. Yagi, Chem. Pharm. Bull. 14, 78 (1966). 26. I. N. Gorbacheva, M. I. Lerner, G. G. Zapesochnaya, L. P. Varnakova, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 27, 3353 (1957). 27. T. Kametani, H. Yagi, and S. Kaneda, Chem. Pharm. Bull. 14, 974 (1966). 28. J. Niimi, Yakugaku Zmshi 80, 123 (1960). 29. H. Kondo, H. Kataoka, and Y. Baka, Annu. Rep. I T S U U Lab. 5 , 59 (1954); C A 49, 14781e (1955). 30. H. Kondo, H. Kataoka, and K. Kigasawa, Annu. Rep. I T S U U Lab. 6, 46 (1955); C A 50, 10113a (1956). 31. W. M. Whaley, L. Starker, and M. Meadow, J. Org. Chem. 19, 833 (1954). 32. W. M. Whaley, L. N. Starker, and W. L. Dean, J. Org. Chem. 19, 1018 (1954). 33. W. M. Whaley, W. L. Dean, and L. N. Starker, J. Org. Chem. 19, 1020 (1954). 34. W. M. Whaley, M. Meadow, and W. L. Dean, J. Org. Chem. 19, 1022 (1954). 35. M. Tomita, K. Fujitani, and T. Kishimoto, Yakugcku Zasshi 82, 1148 (1962). 36. M. Tomita, Y. Inubushi, and Y. Masaki, Japanese Pat. 7121396; CA 76, 59845b (1972). C 1547 (1969). 37. Y. Inubushi, Y. Masaki, S. Matsumoto, and F. Takami, J. Chem. SOC. 37a. S. M. Kupchan, N. Yokoyama, and B. S. Thyagarajan, J. Pharm.Sci. 50,164 (1961). 38. M. Tomita, K. Fujitani, and Y. Aoyagi, Tet. Lett. 1201 (1967). 39. M. Tomita, K. Fujitani, Y. Aoyagi, andY. Kajita,Chem. Pharm. Bull. 16,217 (1968). 39s. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 23, 133 (1975). 39b. T. Kametani, H. Iida, S. Kano, S. Tanaka, K. Fukumoto, S. Shibuya, and H. Yagi, J. Heterocycl. Chem. 4, 85 (1967). 40. E. Fujita and A. Sumi, Chem. Pharm. Bull. 18, 2591 (1970). 41. E. Fujita, A. Sumi, and Y. Yoshimura, Chem. Pharm. Bull. 20, 368 (1972). 42. M. Tomita, Y. Inubushi, and M. Kozuka, Chem. Pharm. Bull. 1, 360 (1953). 43. Y. Inubushi, Chem. Pharm. Bull. 2, 1 (1954). 44. Y. Inubushi and M. Kozuka, Chem. Pharm. Bull. 2 , 215 (1954). 45. M. Tomita and H. Furukawa, Yakugaku Zasshi 83, 676 (1963). 46. M. Tomita and H. Furukawa, Yakugaku Zmshi 84, 1027 (1964). 468. Y. Inubushi, Y. Ito, Y. Masaki, and T. Ibuka, Tet. Lett. 2857 (1976). 47. M. Tomita, S. Ueda, and A. Teraoke, Tet. Lett. 635 (1962). 48. M. Tomita, S . Ueda, and A. Teraoka, Yakugaku Zmshi 83, 87 (1963).
6.
SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS
391
48a. M. Shamma, J. E. Foy, T. R. Govindachari, and N. Viswanathan, J . Org. Chem. 41, 1293 (1976). 49. B. Anjaneyulu, T. R. Govindachari, and N. Viswanathan, Tetrahedron 27,439 (1971). 50. Y.-Y. Hsieh, P.-C. Pan, W.-C. Chen, and Y.-S. Kao, Sci. Sin. 12, 2018 (1964); C A 62, 9184b (1965). 51. Y.-Y. Hsieh, P.-C. Pan, W.-C. Chen, and Y . 3 . Kao, Yao Hsueh Hweh Pao 13, 166 (1966); C A 65, 8979d (1966). 52. T. Kametani, S. Takano, K. Masuko, and F. Sasaki, Chem. Pharm. Bull. 14,67 (1966). 53. M. Tomita, H. Furukawa, T. H. Yang, and T. J. Lin, Tet. Lett. 2637 (1964). 54. T. Kametani, S. Takano, H. Iida, and M. Shinbo, J. Chem. SOC. C 298 (1969). 55. H. Furukawa, Yakugaku Zasshi 85, 335 (1965). 56. A. J. Everett, L. A. Lowe, and S. Wilkinson, Chem. Commun. 1020 (1970). 57. H. M. Sobell, T. D. Sakore, S. S. Tavale, F. G. Canepa, P. Pauling, and T. J. Petcher, Proc. Natl. Acad. Sci. U.S.A. 69, 2212 (1972). 58. L. V. Volkova, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. NaukSSSR 102, 521 (1955); C A 50, 4990i (1956). 59. 0. N. Tolkachev, V. G. Voronin, and N. A. Preobrazhenskii, Zh. Obshch. Khim. 29, 1192 (1958). 60. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 5, 449 (1962); C A 59, 2877e (1963); and V. Voronk, 0. Tolkachev, A. Prokhorov, V. Chernova, and N. Preobrazhenskii, Khim. Geterotsikl. Soedin. 4, 606 (1969); CA 31, 79277p (1970). 61. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. Nauk SSSR 122, 7 7 (1958); C A 53, 1345f (1959). 62. 0. N. Tolkachev, L. P. Kvashnina, and N. A. Preobrazhenskii, Zh. Obshch. Khim. 36, 1764 (1966). 63. E. N. Tzvetkov, I. N. Gorbacheva, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 27, 3370 (1957). 64. V. I. Shvets, L. V. Volkova, and 0. N. Tolkachev, Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 5, 445 (1962); C A 59, 2876h (1963). 65. J. Baldas, I. R. C. Biek, Q. N. Porter, and M. J. Vernengo, Chem. Commun. 132 (1971). 66. H. Hellmann and W. Elser, Ann. 639, 77 (1961). 3531 (1954). 67. M. F. Grundon and H. J. H. Perry, J. Chem. SOC. 68. J. R. Crowder, M. F. Grundon, and J. R. Lewis, J. Chem. SOC. 2142 (1958). 69. M. F. Grundon, J. Chem. Soc. 3010 (1959). C 1024 (1971). 70. T. Kametani, H. Iida, and K. Sakurai, J. Chem. SOC. 71. K. P. Agarwal, S. Rakhit, S. Bhattarcharji, and M. M. Dhar, J.Sci. Ind. Res., Sect. B 19, 479 (1960); C A 55, 16585a (1961). 72. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 15, 1996 (1967). 73. M. Tomita, K. Fujitani, and Y. Aoyagi, Tet. Lett. 4243 (1966). 74. M. Tomita, K. Fujitani, and Y. Aoyagi, Chem. Pharm. Bull. 16, 62 (1968). 75. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 16, 56 (1968). 76. E. S. Pallares and E. M. Garza, Arch. Biochem. 16, 275 (1948). 77. T. Kametani, K. Fukumoto, and M. Ro, Yakugaku Zusshi 84, 532 (1964). 78. T. Kametani, M. Ro, and Y. Iwabuchi, Yakugaku Zasshi 85, 355 (1965). 79. T. Kametani, H. Iida, M. Shinbo, and T. Endo, Chem. Pharm. Bull. 16, 949 (1968). 80. J. Niimi, Yakugaku Zusshi 80, 451 (1960).
392
M A U R I C E SHAMMA A N D VASSIL ST. GEORGIEV
81. J. Niimi, Yakugaku Zasshi 80, 791 (1960). 82. S. M. Kupchan and A. J. Liepa, Chem. Commun. 599 (1971). 83. S. M. Kupchan, A. J. Liepa, V. Kameswaran, and K. Sempuku, J . Am. Chem. SOC. 95, 2995 (1973). 84. For other syntheses of aporphine-benzylisoquinolinealkaloids, see M. Tomita, H. Furukawa, S.-T. Lu, and S. M. Kupchan, Tet. Lett. 4309 (1965); Chem. Pharm. Bull. 15, 959 (1967); R. W. Doskotch, J. D. Phillipson, A. B. Ray, and J. L. Beal, Chem. Commum. 1083 (1969); J . Org. Chem. 36, 2409 (1971). 85. C. Schopf and K. Thierfelder, Ann. 497, 22 (1932). 86. R. Robinson and S. Sugasawa, J. Chem. SOC. 789 (1932). 87. B. Franck, G. Blaschke, and G . Schlingloff, Tet. Lett. 439 (1962). 88. B. Franck and G. Blaschke, Ann. 668, 145 (1963). 89. B. Franck, G. Blaschke, and G. Schlingloff, Angew. Chem., Int. Ed. Engl. 3, 192 (1964). 90. M. Tomita, Y . Masaki, K . Fujitani, and Y. Sakatani, Chem. Pharm. BuZZ. 16, 688 (1968). 91. A. M. Choudhury, I. G. C. Coutts, A. K. Durbin, K. Schofield, and D. J. Humphreys, J. Chem. SOC. C 2070 (1969). 92. See also M. Tomita, Y. Masaki, and K. Fujitani, Chem. Pharm. BuZZ. 16, 257 (1968); M. Tomita, I ( .Fujitani, Y. Masaku, and K.-H. Lee, ibid. 251. C 502 (1969). 93. T. Kametani and I. Noguchi, J . Chem. SOC. 94. Y. Inubushi, Y. Aoyagi, and M. Matsuo, Yet. Lett. 2363 (1969). 95. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC. C 9 (1969). 96. T. Kametani, H. Nemoto, T. Kobari, and S. Takano, J . HeterocycZ. Chem. 7, 181 (1970). 97. J. M. Bobbitt and R. C. Hallcher, Chem. Commun. 543 (1971). 98. M. P. Cava and A. Afzali, J. Org. Chem. 40, 1553 (1975).
-CHAPTER
7 -
THE HASUBANAN ALKALOIDS

YASUO INUBUSHI AND TOSHIRO IBUKA
Kyoto University Sakyo.ku. Kyoto. Japan
I . Introduction ........................................................ I1. Occurrence and Physical Constants of Hasubanen Alkaloids .............. I11 Structure Elucidations ............................................... A . Mass Spectroscopy ............................................... B. Structures of Hasubenan Alkaloids ................................. I T. Synthesis of the Hasubanan Skeleton ................................. A. Synthesis via Ketolactones ........................................ B . Synthesis via'Ketonitriles ......................................... C. Synthesis via Cyclic Enrtmines ..................................... D . Synthesis via Spiroketone .......................................... E . Synthesis by Phenol Oxidation ..................................... V. Synthesis of Hasubanan Alkaloids ..................................... A . Cepharamine .................................................... B. Hasubanonine and Aknadilactem .................................. C. Metaphanine .................................................... V I . Biosynthesis ....................................................... References .........................................................
393 395 395 395 398 414 414 415 416 418 419 419 420 422 424 427 428
I Introduction
Work on alkaloids of the hasubanan group up to 1970 have been reviewed in Volume XI11 of this treatise (1) . I n the succeeding four years that are covered in the present review. significant advances in this field have been made in discovering thirteen new congeners and also in synthetic studies of the hasubanan skeleton and of this type of alkaloids. So far as we know. the occurrence of the hasubanan alkaloids has been noted in Stephania species only. and no alkaloid has been found in other species of Menispermaceae of special interest from the chemotaxonomical viewpoint.
TABLE I PLANT SOURCE AND PHYSICAL PROPERTIES Plant species Alkaloid Metaphanine Stephabyssine Stephaboline Prostephabyssine Stephavanine Cepharamine Delavaine 16-Oxodelavaine Aknadicine Aknadinine Hernandine Methylhernandine Hernandolinol Hernandifoline Hernandoline 3-0-Demethylhernandifoline Protostephabyssine Stephisoferuline Metaphanine Prome taphanine 16-Oxoprometaphanine Homostephanoline Hasubanonine 16-Oxohasubanonine Miersine Stephasunoline Stepham iersine Epistephamiersine Oxostephamiersine Aknadilactam Alrnadinine Constants for hydrobromide. Formula Melting point ("C)
ralD
Reference
Stephania abyssinica Walp.
Stephania cephalantha Hayata Stephania delavayi Diels Stephania hernandifolia Walp.
233 178-180 186-188 196-198' 229-230 186-187 140-150 221-222 156

70
Stephania japonica Miers
Stephania sasakii Hayata
197-199 152-153 114-115 227-227.5 19G191 148-149 196-198" 133-135 232 207a 115 233 116-117 161 222 233 165 98 290 4 210-21
-21 (CHCl,) - 58.9 (CHCI,) +34.7 (MeOH) -105 (MeOH)" + 30 (pyridine) -248 (CHCI,) -240 (CHCI,) -180 (CHCI,) -200 (EtOH) -283 (EtOH) -33 (EtOH) +125 (EtOH) -97.9 (EtOH) -25 (EtOH)
3, 4 5 5 5
6
-105 (MeOH)" +48 (MeOH) -41 (CHCI,) -32 (MeOH)& -52 (CHC1,) -247.8 (CHCI,) -219 (EtOH) - 105.2 (EtOH) 121.4 (CHCl,) +33 (CHCI,) + 64.1 (CHCI,) 88.3 (CHCI,) -189 (CHC1,) -183 (MeOH)b
7 8 9 10-12 10-12 13 14 15 16 17 18 5 19 20-25 26, 27 28 29-31 32-37 38 1, 39 40, 41 40, 41 40, 41 40, 41 10, 42 43
" Constants for methiodide.
7. HASUBANAN ALKALOIDS
395
The numbering system of the hasubanan skeleton (1) (2,3,4,5tetrahydro-3a,9b-butano-l H-benz[e]indole), which is used throughout this review, is that proposed by Tomita et al. in their earlier paper ( 2 , 32).
3
H
1
11. Occurrence and Physical Constants of the Hasubanan Alkaloids

Table I gives a survey of the occurrence and physical constants of hasubanan alkaloids.
III. Structure Elucidations
A. MASS SPECTROSCOPY
From the measurements of IR, UV, and NMR spectra, it is difficult t o determine the hasubanan skeleton of unknown alkaloids. The mass spectral feature, however, exhibits a very characteristic fragmentation pattern and therefore provides a rapid and convenient method for structure elucidation of hasubanan alkaloids, especially that of alkaloids obtained in small amounts (3, 5 , 1 3 , 1 6 , 40).
1 . Hasubanan Derivatives Possessing No Oxygen Function at C Ring
I n the mass spectra of 3,4-dimethoxy-N-methylhasubanan(2), 3-methoxy-4-hydroxy-N-methylhasubanan (3), and lO-oxo-3,4-dimethoxy-N-methylhasubanan (4), the most abundant and diagnostic peak appears at m/e M-56. The first rupture occurs in ring C to furnish an ion, a or e . The additional loss of methyl or hydrogen from the fragment ion a must give rise to ion b or c and the loss of a methoxyl radical from the ion c produces ions d and/or d'. The fragmentation pattern of these compounds is a primary breakdown path for all hasubanan alkaloids (44, 45).
396
&
OMe
rJ*
_3
; . 1 9
OMe
+ /
fN
I
Me
a
Me
d
2 3
Me R=Me
R = H
m/e 245 ( R = Me) M-56
m/e 213
(?Me
OMe
I
OMe
I
Me Me
Me
&&
b
m/e 230
c
m/e 244
d'
rn/e 213
OMe
__f
+/
u:
tN
Me
4
Me
m/E 259 e' m/e 259
Me
e
SCHEME 1
2. Alkaloids Possessing a Hemiketal or .a Ketal Ether Linkage between C-8-C-10: Metaphanine ( 5 ) and Stephamiersine (6)
The mass spectrum of metaphanine ( 5 ) (3, 20, 21, 44) exhibits the most abundant ion peak (a or a') a t m/e 245, which may arise from the intermediate f by homolysis of the C-5-C-13 bond and the associated hydrogen transfer from C - 5 or C-6 to C-10 or (2-13. The hydro,aen source
7.
HASUBANAN ALKALOIDS
397
and the mechanism of this hydrogen transfer, however, are uncertain. The ion a may derive further stabilization by the loss of hydrogen to a fragment ion g a t m l e 2 4 4 . Alternatively, the ion a t m/e 244 may also occur from the intermediate f through the simple homolysis of the C-5-C-13 bond, and the structure h could be proposed for this ion. Another significant ion, i is observed a t m/e 243, and this ion may be
.......
10
/
\ +
Me
Me
5
a mle 245
1
Me
h m l e 244
i mle243
Me
g
mle244
Me
R1 = H, R, = OMe 7 R1 = OMe, R2 = H
6
SCHEME 2
398
derived from the intermediate f by the loss of hydrogen and the associated C-5-C-13 bond fission (5, 40, 44, 45). The cleavage mode mentioned above is quite common for all metaphanine type alkaloids possessing an ether linkage between c-8and C-10, and a ketone function at (2-7. By contrast, the fragmentation of stephamiersine (6) and epistephamiersine (7)) which possess an ether linkage between C-8 and C-10 and a ketone function a t C-6, produces the most abundant ion, i, at mle 243 rather than an ion a' a t m/e 245. This difference may be of diagnostic significance, as it demonstrates the presence of a ketone function a t C-6 in metaphanine type alkaloids (4U). 3. Alkaloids Possessing an +Unsaturated Ketone Group a t C Ring: Iso-6-dehydrostephine (8) and Hasubanonine (129) Alkaloids such as hasubanonine (129), possessing an a,/?-unsaturated carbonyl group a t C ring, show a similar breakdown pathway as that of metaphanine and others. An important feature of the spectra of these alkaloids is that two intensive ion peaks are observed-one is an ion a or a' and the other is an ionj, which occurs by the loss of the ethanamine chain from the molecule. I n the case of isodehydrostephine (8)) the most abundant ion peak, j, was found a t mle 301 ( 6 ) .
0 1
+
H
8
mle 301
SCHEME 3
B. STRUCTURES OF HASUBANAN ALKALOIDS

1. Stephisoferuline (9)
Stephisoferuline was isolated from Stephania hernandifolia, and the presence of four methoxyl groups, one secondary amino group, an a$-unsaturated ester moiety, and two phenolic hydroxyl groups was shown (19).A new hasubanan ester-ketal structure (9) was assigned to
7.
HASUBANAN ALKALOIDS
399
stephisoferuline on the following evidence. Hydrolysis of stephisoferuline afforded stephuline (10) and isoferulic acid. The former gave N-methylstephuline (11) on methylation, confirming the presence of a secondary amino group. Treatment of 10 with dilute hydrochloric acid led t o facile demethylation of acetalmethyl t o give 8-demethylstephuline (12) and oxidation of 10 with Jones reagent provided 6-dehydrostephuline (13). On the other hand, acetylation of 10, followed by acid treatment, resulted in the triacetyl derivative 14, and the downfield shift of the signal for the C-7 H (6 4.20) of 14 in its NMR spectrum compared with that of stephisoferuline (6 3.75) supported the assignment Hydrogenation of the triacetyl derivative of the ketone function a t C-8. 14 furnished the dihydrotriacetyl derivative 15, which on treatment with acetone dimethylacetal in the presence of p-toluenesulfonic acid afforded the rearrangement product 16. The compound 16 was identified with the base derived from aknadicine ( = 4-demethylnorhasubanonine) (17) ( 1 0 , 1 1 ) as follows. Reduction of 17 with NRH gave the C-6 epimeric alcohols 18. Acetylation of 18 gave the products that were converted t o the triacetyl derivative 16 by letting their chloroform solution stand. This chemical correlation established the planar structure of stephisoferuline, the stereochemistry a t C-8, C-10,C-13,and C-14, and the absolute configuration of the molecule. Since reduction of 6-dehydrostephuline (13) with NBH gave stephuline (10)solely, and the hydride attack from the a side of 13 was predictable from inspection of the molecular model, the /3 configuration of the C-6 hydroxyl group was suggested. On the other hand, chemical, spectral, and crystallographic examinations suggested the same configuration of five of the six asymmetric centers of stephisoferuline (9) with those of stephavanine (19) ( 6 ) .From the biogenetic analogy, the /3 equatorial configuration of the C-7methoxyl group of 9 was presumed (19).
OMe
H
9
10 11 12
R2 R, = Me, R, = H R, = R, = M e R 1 = R, = H
400
Me0
k
H
18
A C
14
Ac
15
AcO
Me0 Me0 N Ac
16
\
Me0 N
H
17
H
1s
2. Stephavanine (19)
Stephavanine was isolated from Stephania abyssinica grown in Eastern and Southern Africa, and the presence of one methylenedioxy, two hydroxyl, one secondary amino, and two methoxyl groups in its molecule was shown ( 6 ) .The mass spectrum of stephavanine revealed a diagnostic fragment ion k for hasubanan alkaloids at m/e 214 (44,45). Alkaline hydrolysis of stephavanine gave vanillic acid and stephine (20), and the 6,7-bistrirnethylsilyl ether 21 was derived from the latter. The NMR spectrum of 21 showed two unsplit aromatic proton signals, indicating the methylenedioxy group attached to C-2 and C-3 of an aromatic ring. Oxidation of 20 with Jones reagent provided 6-dehydrostephine (22), which on treatment with sodium hydroxide solution gave isodehydrostephine (8). Of six chiral centers of 19, the relative configurations of C-8, (2-10, C-13, and C-14 were inevitably established because of the cage ring system of the stephavanine moIecuIe. The /%axial configuration of the C-6 hydroxyl, which forms an ester linkage with vanillic acid, was deduced from the NMR spectral examination and the /I-equatorial configuration of the C-7 hydroxyl group was suggested
40 1
by the fact that oxidation of the diol20 provided selectively the monoketone 22. Thus, the structure 1 9 was assigned t o stephavanine (6). This conclusion was supported by X-ray crystallographic study of stephavanine hydrobromide ( 6 ) .
Me0
RO
"H
Me0 N
H
19
H 20 R = H 21 R = &(Me),
?"\
c #
+/
"H
Me0 N
H
22
mle 214
3. Stephabyssine (23), Stephaboline (24), and Prostephabyssine (25)
Examination of basic constituents of Stephania abyssinica. collected in Ethiopia resulted in the isolation of three new phenolic hasubanan alkaloids-stephabyssine, stephaboline, and prostephabyssine ( 5 ) . Stephabyssine (23) had one N-methyl, one methoxyl, one saturated ketone, and two hydroxyl groups. The presence of a phenolic hydroxyl group with an unsubstituted para position was presumed by a positive color reaction with Gibbs' reagent. Methylation of 23 with methyl iodide in the presence of potassium carbonate provided O-methylstephabyssine, which was identified with metaphanine ( 5 ) (4,20-25, 46, 47). Thus, the structure of stephabyssine was established as 4-demethylmetaphanine (23).
402
OMe
OMe
J 3.. 3 . $.H .
"H
HO N
HO
"H
HO N
I
I
I
I
Me 23 R = H 5 R=Me
Me
24
Stephaboline (24) was shown to possess one N-methyl, one methoxyl, and three hydroxyl groups ( 5 ) . The close relationship of stephaboline with stephabyssine (23)was indicated by similarities in their NMR spectra as well as positive reactions of each compound with ferric chloride and the Gibbs reagent. Since NBH reduction of stephabyssine gave stephaboline in a high yield, the structure of stephaboline was established except for the configuration of the C-7 hydroxyl group. The NMR spectrum of 24 exhibited a diffused multiplet a t S 4.4 assignable to the C-7 H. This signal changed to a pair of doublets (JAx = 5 Hz, J B X = 1 1 Hz) by treatment with D,O, and the magnitude of the coupling constant of J B X suggested the axial configuration of the C-7 H,thus confirming the equatorial configuration of the C-7 hydroxyl group (5). When treated with aqueous hydrochloric acid solution under mild conditions, prostephabyssine (25) gave stephabyssine (23)with loss of the elements of methanol in high yield. This facile hydrolysis demonstrated the presence of an enol methyl ether located at C-6-(2-7. Consequently, the structure 25 was assigned to prostephabyssine. Determination of the NMR spectra of prostephabyssine in a variety of solvents gave complex patterns indicative of the presence of the hemiketal25a and ketone 25b forms in equilibria similar to the solvent-dependent equilibria observed in prometaphanine (26,27).
?Me
?Me
OH HO N
I
Me
258
I
25
Me 25b
SCHEME 4
7.
HASUBANAN ALKALOIDS
403
4. Stephamiersine (6), Epistephamiersine (7), Oxostephamiersine (26),
and Stephasunoline (28) Reinvestigations of basic constituents of Stephania japonica grown in Kagoshima Prefecture (the sourthern part of Japan) resulted in isolations of four new hasubanan alkaloids: stephamiersine, epistephamiersine, oxostephamiersine, and stephasunoline (40, 41). That the structures of these alkaloids were closely related to each other was presumed on the basis of their spectral data which are summarized in Table I1 and Table 111.
TABLE I1 PHYSICAL CONSTANTS AND SPECTRAL DATA OF SOME ALKALOIDS FROM Stephania japonica Miers mp ("C) 165 98 290 233
[aID
A1kaloid
Stephamiersine (6) Epistephamiersine (7) Oxostephamiersine(26) Stephasunoline (28)
(CHCl,) +33
IR 3 Y ' : 7 : (cm-') 1725 1735 1730, 1680 3550
W (nm)
286 286 286 286
AEtoH msx
(6)
MS (mle) M+,
base peak 389,243 389,243 403,257 377,245
+ 64.1
+88.3 $121.4
2200 2300 2000 2000
TABLE I11 NMR SIGNALS OF SOME ALKALOIDS FROM Stephania japonica Miers4 Aromatic protons (2H) 6.67 6.66 6.77 6.67
Alkaloid
6 7 26 28
O
C-7-H
3.52 4.27 3.63 3.62
C-10-H
4.72 4.82 4.79 4.88
Methoxyl groups 3.92, 3.89, 3.92, 3.90, 3.82, 3.76, 3.83, 3.82, 3.34, 3.31 3.52, 3.45 3.33, 3.29 3.46
N-Methyl group 2.64 2.63 3.12 2.57
Chemical shifts are quoted in 6 values.
Equilibrium experiments of either stephamiersine (6) or epistephamiersine (7) with 1yosodium hydroxide solution gave an equilibrium mixture consisting of 6 and 7 in a 1:3 ratio. Consequently, 6 and 7 were epimers attributable to an asymmetric center adjacent to a carbonyl group, and 7 was thermodynamically more stable. Furthermore, permanganate oxidation of stephamiersine (6) gave the lactam, which was identified with oxostephamiersine (26). Reduction of epistephamiersine (7) with NBH provided dihydroepistephamiersine (27),* which on treatment
* Later. this compound waa obtained in nature from Stephuniu abyssinica by Dr. A. J. von Wyk.
404
with methanolic hydrochloric acid solution under mild conditions gave stephasunoline (28). This facile hydrolysis of dihydroepistephamiersine suggested the presence of the labile acetal methyl ether in its molecule. Thus, the chemical correlations among 6,7,26, and 28 were established. Acetolysis of stephamiersine (6) and epistephamiersine (7) provided 1,3-diacetoxy-2,5,6-trimethoxyphenanthrene (29) and 1,2,3-triacetoxy5,6-dimethoxyphenanthrene (30), respectively. On the other hand, acetolysis of dihydroepistephamiersine (27) gave the known 1-acetoxy2,5,6-trimethoxyphenanthrene (31) (26,27). On the occasion of acetolysis of morphinan and hasubanan series alkaloids, it is well known that a ketone function in the original molecule remains an acetoxyl group on the phenanthrene nucleus, and an alcoholic hydroxyl group is removed by dehydration in the course of the aromatization process ( 2 0 , 2 1 , 2 6 , 2 7 ,4 1 , 4 8 , 4 9 ) . From the structures of these phenanthrene derivatives derived from 6 , 7 , and 27, the positions of five of six oxygen functions were confirmed, and particularly, the C-3, C-4, and C-7 positions of three of four methoxyl groups and the C-6 position for an oxygen function in the original alkaloid molecule were established. I n the NMR spectra of 6 , 7 , and 28, a signal due to C-10 H appeared around 6 4.8 (doublet, J = 6.5 Hz). I n the spectrum of 7, the NOE [ I3y0 enchancement of the signal of this doublet ( 6 4.82)] was observed when irradiated a t the aromatic proton signal. The signals at 6 1.47 (doublet,J = 10.5 Hz) and 6 2.46 (double doublet, J = 10.5 and 6.5 Hz) were assigned to the C-9 methylene protons by the double resonance technique. From these assignments, it is obvious that an acetal ether linkage attaches to C-10. NBH reduction of oxostephamiersine (26) provided compound 33, which on treatment with perchloric acid-acetic anhydride gave compound 34. Oxoepistephamiersine (32) derived from epistephamiersine (7) by permanganate oxidation was reduced with NBH t o give compound 35, which on treatment with perchloric acid-acetic anhydride also afforded compound 34. Catalytic hydrogenation of 34 provided the conjugated ketone 36. On the other hand, NBH reduction of 16oxohasubanonine (37) (28, 38) gave epimeric alcohols (38), which on treatment with dilute mineral acid gave the same conjugated ketone 36. From these results, the skeletal structure and the attached positions of oxygen functions, C-6, C-7, C-8, and C-10 of oxostephamiersine (26) were established. The configurations of the C-7 OCH, group of these alkaloids were deduced from the NMR spectral experiments. I n the spectrum of stephamiersine (6), signals due t o the C-5 methylene protons were observed at 6 2.86 ( l H , double doublet, J = 11.5, 1.5 Hz) and 6 3.67
7.
HASUBANAN ALKALOIDS
405
( l H , doublet, J = 11.5 Hz). The long-range coupling between the C-7 H and one of two C-5 methylene protons ( 6 2.86) was observed by the homonuclear INDOR technique. On the other hand, the spectrum of revealed signals assignable to the C-5 methylene epistephamiersine (7) protons at 6 2.99 (IH, doublet, J = 11.5 Hz) and 6 3.18 (IH, doublet, J = 11.5 Hz) and the NOE (6.5y0 enhancement) of the C-7 H signal was observed when irradiated the signal a t 6 3.18 but no signal enhancement was observed between the C-7 H and the signal at 6 2.99. From these findings, together with the equilibrium experiments previously discussed, the configuration of the C-7 OCH, was established to be aaxial in 6 and p-equatorial in 7. The configurations of C-6 OH and C-7 OCH, of stephasunoline (28) were also deduced from the NMR spectral examinations. The spectrum of stephasunoline exhibited signals assignable to the C-5 methylene protons a t 6 2.46 (IH, double doublet, J = 14.3, 2.4 Hz) and 6 2.82 ( l H , double doublet, J = 14.3, 3.8 Hz). When irradiated a t the signal appearing a t 6 2.46, the NOE (120J, enhancement) of the C-7 H signal (6 3.62, doublet, J = 3.9 Hz) was observed. This result, together with analysis of coupling constant values of the signals for four protons attached to C-5, c-6, and C-7, led to the conclusion that the C-7 OCH, group should be p-equatorial and the C-6 OH p-axial. Thus, the structure 28 was assigned to stephasunoline (40, 41). The planar structure of stephasunoline (28) is the same as that proposed for miersine (39)but the stereochemistry of C-6 OH and C-7 OCH, of the latter has not been established (1,39).
5 . 16-Oxohasubanonine (37)
This alkaloid was isolated from Stephania japonica and identified with 16-0xohasubanonine, which had been derived from hasubanonine by permanganate oxidation (28, 38).
6. 16-Oxoprometaphanine (40)
This alkaloid was isolated from Stephaniajaponica (28).On hydrolysis with dilute mineral acid 16-oxoprometaphanine gave known oxometaphanine (41) (50, 51) and compound 34, which had been derived from stephamiersine (6) and epistephamiersine ( 7 ) (40, 41). Acetylation of 16-oxoprometaphanine gave acetyl-16-oxoprometaphanine (42), which on treatment with dilute hydrochloric acid afforded compound 34. These chemical correlations and the NMR spectral examinations of 16-oxoprometaphacine and its transformation products supported the structure 40 for 16-oxoprometaphanine (28).
406
J
0-
J
0-
- J t-+
U
-J
On4
0-
i
+
;bi
Ot...? O ?
-3 a
2
(0
7.
HASUBANAN ALKALOIDS
407
T
El
\
L
1
r" O-GpJ-
w-
H
0
408
?Me
?Me
Me0
Me
40s
40
SCHEME 6
@
0
HO Fi
Me
41
&
OAc
Me 40b
. .
.H
Me0 O N
Me
42
7. Delavaine (43)
Delavaine was isolated from Stephania delavayi (8) and its IR spectrum exhibited bands a t 1670 cm- (cr,p-unsaturatedketone) and 1608 cm-l (C=C double bond) (8). Hydrolysis of the methylenedioxy group of delavaine with sulfuric acid and phloroglucinol gave the corresponding dihydroxy derivative 46, which on acetylation afforded the diacetyl derivative 47. The I R absorption of the ester carbonyl (17751780 c m - l ) in 47 showed the phenolic nature of the hydroxyls, from which it follows that the methylenedioxy group is attached to an aromatic ring. On the other hand, the NMR spectrum of delavaine exhibited two unsplit aromatic proton signals a t 6 6.41 and 6 6.64. Consequently, it is obvious that the methylenedioxy group is a t the C-2 and C-3 position of the aromatic ring. The Hofmann degradation of delavaine methiodide formed the methine base 44,which on acetolysis furnished the acetoxy-methoxy-phenanthrene derivative 45 (8), suggesting that delavaine belongs to the hasubanan alkaloids. In the NMR spectrum of delavaine, signals were present for N-methyl (6 2.49) and methoxyl(6 4.06 and 6 3.60) groups, and the C-5 methylene proton
7.
HASUBANAN ALKALOIDS
409
Me0 M eO 0 & 0 M e 0/ N\
Me
43
Me
44
Me
Me
45
46 47
R = H
R = Ac
signals appeared a t 6 2.46 (doublet, J = 16 Hz) and 6 3.00 (doublet, J = 16Hz). However, no C-9 H signal of the morphinan skeleton between 6 3.00 and 6 4.00 (52-55) was observed, thus demonstrating the hasubanan skeleton for delavaine. Consequently, structure 43 was proposed for delavaine (8), but no positive evidence regarding the stereochemistry of the ethanamine bridge is presented.
8. 16-Oxodelavaine (48)
16-Oxodelavaine was isolated from Stephunia delavayi grown in Transcaucasia (9).The UV spectrum of this alkaloid was similar to that of delavaine (8), and the IR spectrum showed bands for an a,/?unsaturated ketone (1686 cm-') and a lactam carbonyl (1670 cm-l) function. I n the NMR spectrum, signals were present for two isolated aromatic protons ( S 6.64, 1H, singlet and S 6.46, 1H, singlet),methylenedioxy ( 6 5.88, 2H, singlet), two methoxyl ( 6 4.10 and 3.66 each 3H and singlet), and an N-methyl (6 2.96, 3H, singlet) groups, and the c-5
410
methylene protons (6 2.90, lH, doublet, J = 16 Hz and 6 2.66, l H , doublet, J = 16 Hz). After various chemical, physicochemical, and spectral investigations, the structure 48 was proposed for 16-oxodelavaine (9).
Me
48
9. Hernandifoline (49) Hernandifoline was isolated from Stephania hernandifolia grown in t h e Black Sea littoral of Caucasia (16).The presence of four methoxyl, one secondary amino, two hydroxyl, and one a,p-unsaturated ester groups was shown. Methylation of hernandifoline (49) with methyl iodide afforded A'-methylhernandifoline (50), and alkaline hydrolysis of 49 gave a base (51) and hesperetic acid. The NMR spectrum of 51 revealed signals for two aromatic protons (6 6.49, 2H, singlet), C-10 H (6 4.76, doublet, J = 5.8 Hz), C-6 H (6 4.07, multiplet), C-7 H ( 6 3.62, doublet, J = 4.0 Hz), C-3 OCH, (6 3.67, singlet), C-8 OCH, (6 3.50, singlet), C-7 OCH, (6 3.38, singlet), C-5 methylene protons (6 3.04, 1H, quartet, J = 14.9, 3.5 Hz and 6 1.85, 1H, quartet, J = 14.9, 2.8 Hz), C-6 OH (6 2.13, l H , doublet,J = 10.0 Hz), C-9 methylene protons (6 2.34, 1H, quartet, J = 10.8, 5.8 Hz and 6 1.80, lH, doublet, J = 10.8 Hz). The mass spectrum of 51 showed the pattern characteristic for the hasubanan alkaloids (44),m/e 363 (M+), 217, and 216. Methylation of 51 with methyl iodide in methanol gave substance 52 and the further methylation of 52 with diazomethane gave compound 53. Following spectral investigations of the alkaloid and its degradative compounds, the structure of hernandifoline except the configuration at the C-7 OCH, group was proposed as 49 (16). This structure is the same as that proposed for stephisoferuline (9) (19),except for the configuration of the C-7 OCH, group. The reported melting points of hernandifoline (49) (227-227.5"C), the compound (51) (225-226"C), and the compound (52) (154-155C)
7.
HO
HASUBANAN ALKALOIDS
41 1
M00Q7=~Lo@ / \ H
H o &
Me0
Me0 N
R
49 50
. .
'.H
Me0
.
*
:
I
.H
Me0
R = H R = Me
R2 5 1 R, = R, = H 52 R, = H, R, = Me 53 R, = R, = Me
differ from those of stephisoferuline (9) (133-135OC), stephuline (10) (223-225C)) and N-methylstephuline (11) (126-128%), but there has been no report of direct comparisons of these alkaloids.
10. 3-0-Demethylhernandifoline (54)
3-0-Demethylhernandifoline was isolated from Stephania hernandifolia, and the presence of three hydroxyls, one secondary amino, and three methoxyl groups was shown (18). The IR spectrum exhibited bands for OH and NH a t 3560, 3440, and 3200-2700 cm-l, a carbonyl group at 1695 crn-l, and a conjugated double bond a t 1640 cm-l. I n the NMR spectrum signals were present for three methoxyls (6 3.89, 3.41, and 3.40), ortho-coupled aromatic protons (6 6.50, l H , doublet, J = 8.0 Hz and 6 6.60, 1H, doublet, J = 8.0 Hz), the C-5 methylene protons (6 2.02, l H , double doublet, J = 15.0, 2.3 Hz and 6 3.17, 1H, double doublet, J = 15.0, 4.1 Hz), C-6 H (6 5.40, l H , multiplet), C-7 H (6 3.74), and C-10 H (6 4.88, lH, doublet, J = 5.8 Hz). On alkaline hydrolysis, 3-0-demethylhernandifoline gave hesperetic acid and an amine (55))which gave an intense color reaction with ferric
I H
54
H
55
412
chloride characteristic for o-phenols. Methylation of 55 with methyl iodide, followed by treatment with diazomethane, furnished the N,O,O-trimethyl derivative, which was identical with compound 53 (16) derived from hernandifoline. From these chemical correlations, structure 54 was proposed for 3-0-demethylhernandifoline.
11. Hernandine (56)
Hernandine was isolated from Xtephania hernandifolia, and the presence of one N-methyl, two methoxyl, and three hydroxyl groups was suggested (13).The mass spectrum of this alkaloid revealed a characteristic fragment ion peak for hasubanan alkaloids a t m/e 231 (13, 44, 45). The NMR spectrum of hernandine showed signals for C-10 H (8 4232,
OMe
I
. :/J R20 N
Me 56
or
R, = H, R, = Me R, = Me, Ra = H
1H, doublet, J = 6.2 Hz), C-9 methylene protons (8 1.51, l H , doublet, J = 10.8 Hz and S 2.85, 1H, double doublet, J = 10.8, 6.2 Hz), C-6 H ( 6 4.15, lH, multiplet), C-7 H (8 3.58, l H , doublet, J = 3.8 Hz), and C-5 methylene protons (6 3.09, l H , double doublet, J = 14.6, 3.5 Hz and 6 1.95, lH, double doublet, J = 14.6, 2.4 Hz). The axial configuration of C-6 OH was determined from the values of the spin-spin coupling between the C-5 methylene protons and c-6 H. From these results, structure 56 was proposed for hernandine (13),but the absolute
configuration of the ethanamine bridge, the configuration of the C-7 oxygen function, and the position of one of two methoxyl groups have not been definitely established.
12. Methylhernandine (57)
Methylhernandine was isolated from Stephania hernandifolia, and the presence of one N-methyl, two hydroxyl, and three methoxyl groups was suggested (14). On acetylation, methylhernandine gave diacetyl-
7.
HASUBANAN ALKALOIDS
413
methylhernandine, the IR spectrum of which showed carbonyl bands a t 1775 and 1730 cm-l, indicating that one of two hydroxyl groups is phenolic and the other alcoholic. I n the NMR spectrum of methylhernandine, signalswere present for C-5 methylene protons (S 1.93,lH, double doublet, J = 14.8, 2.9 Hz and 6 3.00, l H , double doublet, J = 14.8,
Me0 N
: :/
Me
57
3.4 Hz), C-6 H (6 4.05,lH, multiplet), C-6 OH (6 2.24, doublet, J = 9.8 Hz), C-7 H (6 3.62, l H , doublet, J = 4.1 Hz), C-10 H (6 4.81, l H , doublet, J = 6.2 Hz), and C-9 methylene protons (6 1.45,1H, doublet, J = 10.8 Hz and 6 2.63, lH, double doublet, J = 10.8, 6.2 Hz). Since
methylhernandine was identified with compound 52 (16) derived from hernandifoline (49) (16), structure 57 was proposed for methylhernandine (14).
1 3. Hernandolinol (58)
Hernandolinol was isolated from Stephunia hernandifolia grown in Caucasia, and the presence of one N-methyl, three methoxyl, and two hydroxyl groups was suggested. On Hofmann degradation, hernandolin01 gave the methine base (mp l14-115C), which on acetolysis afforded the diacetoxydimethoxyphenanthrene derivative (mp 163164OC) (15). This methine base and phenanthrene derivative were
OMe
Me
58
414
identified with the methine base and phenanthrene derivative derived from hernandoline, respectively (I?'),and hernandolinol was proved to be identical with the reduction product of hernandoline with sodium borohydride. Thus, structure 58, without stereochemical implications, was proposed for hernandolinol (15).
IV. Synthesis of the Hasubanan Skeleton

The synthesis of the hasubanan skeleton has been undertaken in several laboratories with a remarkable degree of variability in the synthetic schemes.
VIA KETOLACTONES A. STNTHESIS
Annelation reaction of the ketoester 59 with methyl vinyl ketone provided the ketolactone 60. Three methods available for introduction of the nitrogen atom into this ketolactone have been reported. The first method was reported by Inubushi et al. Treatment of the ketal lactone 61 from the ketolactone 60 with methylamine in the presence of methylamine hydrochloride gave the ketolactam 63 and the ketal amide 68 (56-58). Similarly, the ketoester 64provided the ketal lactone 66 and the ketolactam 67 via the ketolactone 65. The second method was developed by Evans et al. Reaction of the ketolactone 60 with methyl iodide in the presence of potassium carbonate gave the unsaturated ketoester 62, which on treatment with LAH-methylamine furnished the ketolactam 63 ( 5 9 , 6 0 ) .The last method was reported by Tahk et al. Reaction of the ketal lactone 61 with a large excess of methylamine gave the ketal amide 68, which was reduced with LAH to give the amino alcohol 69, acid
R
59 R = H 64 R = OMe
60
R = H 65 R = OMe
61 R = H 66 R = OMe
415
Me
62 63 67
Me
68 69
R = H R = OMe
R = O R = Hz
Me
70
treatment of which afforded 7-0x0-N-methylhasubanan (70) (61, 62). The main disadvantage of these three methods was the low yield in the nitrogen introduction step.
B. SYNTHESIS VIA KETONITRILES

This procedure consists in the Robinson annelation reaction of the ketonitrile (71 or 72) with methyl vinyl ketone. Treatment of the ketonitrile 71 with methyl vinyl ketone provided the separable stereoisomeric mixture 73. Treatment of the mixture with sodium alkoxide
NC 0
4 Nc8 &
OH
Mo
73 74
OH
H
75 76
71 72
R = H = OMe
R = H
R = OMe
R = H R = OMe
416
gave the ketolactam 75. Similarly, the ketonitrile 72 gave the ketolactam 76 (57, 58). This procedure is of practical value because of acceptable yields and simpler operations compared with the former methods.
C. SYNTHESIS VIA CYCLICENAMINES

1. Stork-Robinson Annelation Reaction
Synthesis of the key intermediate, the cyclic enamine 79, is analogous to that of 3-arylpyrroline in the mesembrine synthesis (63-65). Three methods available for synthesis of this intermediate have been developed. Reaction of /3-tertralone (77) with 1,2-dibrornoethane gave the spiroketone 78, which on treatment with methylamine furnished the cyclic enamine 79 (61).On the other hand, ketalization of the ketoester
Me
77 59
R = H R = CH,CO,Et
78
79
Me
80 81
59, followed by treatment with LAH-methylamine, afforded the ketal
amide 80. Successive treatments of 80 with LAH and aqueous acid solution provided the cyclic enamine 79 (59, 60). Further, reaction of p-tetralone (77) with excess methylamine, followed by treatment with titanium tetrachloride, yielded the enamine 81. When reacted with isopropylmagnesium chloride, this enamine gave the "bidentate" nucleophile which on treatment with bromochloroethane gave the cyclic enamine 79 (60). The cyclic enamine 79 thus synthesized was reacted with methyl vinyl ketone to yield 7-oxo-N-methylhasubanan (70) in a moderate yield (60-62).
7. HASUBANAN ALKALOIDS 2 . [4
417
+ 21 Cycloaddition and [2,3] Sigmatropic Rearrangement
A unique and elegant synthesis of hasubanan derivatives was reported by Evans et al. (66).Upon heating equimolar quantities of the sulfoxide 82 with the cyclic enamine 79,a diastereoisomer mixture of the sulfoxide 83 as well as some rearrangement amino alcohol 84 was obtained, indicating that [4 + 21 cycloaddition and [2,3] sigmatropic rearrangement were occurring consecutively. When heated with sodium sulfite, the unpurified reaction product from 79 and 82 afforded the
<
R
82
. .
C,H,-S
N
0 Me R = S-CSH,
83
$ 1
0
85
J.
= C0,Me
Me
84
Me
86
desired amino alcohol 84. The evidence that 84 is a single isomer rather than an epimeric mixture was derived from its behavior on tlc, its cleanly resolved NMR spectrum, and the sharp melting range of the amine salt. The syn relationship between hydroxyl and nitrogen function was deduced from the observance of intramolecular hydrogen bonding in the IR spectrum. Similarly, addition of methyl pentadienoate to the cyclic enamine 79 was also found to afford the nicely crystalline tetracyclic ester 86 in 50% yield. Qualitatively, it appeared that the sulfoxide-substituted diene 82 was slightly less reactive than the estersubstituted diene 85 ( 6 6 ) .
418
D. SYNTHESIS VIA SPIROKETONE

Another synthetic route for hasubanan derivatives was devised recently by the Bristol-Myers group. Alkylation of 7-methoxytetralone (87) with 1,4-dibromobutanein the presence of sodium hydride gave the
87
88
89 90
R R
= CN = CH2NH,
OMe
I
(-yg
I
OMe
.
I
H
91
Br
92
spiroketone 88, which was transformed into the hydroxynitrile 89 by treatment with acetonitrile in the presence of n-butyllithium. LAH reduction of 89 furnished the amine 90, which on treatment with concentrated hydrochloric acid gave the amine 91. Treatment of 91 with (92) one equivalent of bromine yielded 3-methoxy-9-bromohasubanan in good yield (67, 74). A new synthetic method of dl-3-methoxy-N-methylhasubanan has been explored recently (75). Treatment of 91 with formalin in formic acid afforded dl-9,10-dehydro-3-methoxy-N-methylhasubanan, which by catalytic was derived into dl-3-methoxy-N-methylhasubanan hydrogenation (75).
419
E. SYNTHESIS BY PHENOL OXIDATION

Treatment of reticuline (93) with trifluoroacetic anhydride, followed by catalytic hydrogenation yielded the amide 94. Treatment of 94 with vanadium oxytrichloride gave rise, by phenol oxidation, to the dienone 95, which was transformed into the enone 96 by treatment with aqueous potassium carbonate solution. When reacted with methanolic hydrochloric acid, the enone 96 provided the cepharamine analog 97 (68).
Me0
HO
Me
,
'COCF3
Me0
"")y u
Ho
Md3(3
/
95
OMe
Me0
93
94
OMe
OMe
Me
96
Me
97
V. Synthesis of Hasubanan Alkaloids

The syntheses of hasubanan alkaloids are of interest in connection with their pharmacological activities, since these alkaloids involve the structural unit of prafadol (98) (69),which is used as a potent analgesic. Hasubanan alkaloids are classified into three groups-the cepharamine, hasubanonine, and metaphanine types-on the basis of the oxidation stage at the B and C rings. The representative of each group has been synthesized from the common intermediate, the ketolactam 67, with an exception of one of two cepharamine syntheses.
420
A. CEPHARAMINE
Methylation of the ketal99 derived from the ketolactam 67 (Section IV,A) with methyl iodide provided the ketal lactam 100. Since cepharamine (108) possesses a methoxyl group at C-3 and a hydroxyl group a t C-4, a partial demethylation step in the course of the synthetic route is required. When heated with potassium hydroxide and hydrazine in ethylene glycol ( 5 0 , 5 1 , 5 6 , 5 7 ) ,the ketal lactam 100 gave two kinds of phenols-101 (major) and 102 (minor). Acetylation of 101, followed by deketalization, provided the keto acetate 104, which on treatment with two equimolar quantities of bromine, followed in turn by heating with sodium acetate in acetic acid, gave an inseparable mixture consisting of the desired diketone 105 and an unidentified compound in a 1:1 ratio. Methylation of this mixture and separation of the reaction mixture furnished 16-oxocepharamine acetate (106) in a pure state. Reduction of 106 with LAH provided the epimeric alcohols (107), which on oxidation with DMSO-DCC-phosphoric acid (70) gave cepharamine (108) (57, 58, 62).
OH
OMe
OMe
Me
R
9s
99
R = H
100 R = Me
Me 101 R = H 103 R = AC
& c
OH
\
OMe
?Me
Me
Me
Me
102
104
106
OMe OMe
42 1
OMe
Me
106
Me
107
Me
108
Another synthetic route to cepharamine utilizing photocyclization was designed. Heating of 2-bromoreticuline (109) with trifluoroacetic anhydride, followed by catalytic hydrogenation, provided the dihydromethine 110. Irradiation of 110 with a mercury lamp in the presence of sodium hydroxide and sodium iodide gave the dienone 111. Hydrolysis of the amide function of 111 caused the Michael addition to yield an isomer of cepharamine. Transesterification of 112 with hydrochloric acid in methanol provided a mixture of cepharamine (108) and the starting material 112, from which cepharamine was isolated in a pure state (71).
Me0
HO HO
H
Me0
o
109
yJJ
Me0 ?Me Me 0 0
Me0
&
110
COCF,
111
Me
112
422
B. HASUBANONINE AND AKNADILACTAM

I n the synthesis of hasubanonine (129) from the ketolactam 67, introduction of two more oxygen functions a t the C-6 and C-8 positions are required. Oxidation of the ketolactam 67 with lead tetraacetate in the presence of boron trifluoride etherate gave three acetates-l13,114, and 115. In order to avoid the production of the undesired acetates 114 and 115, a lowering of the electron density of an aromatic ring was preferable. Thus, similar oxidation of the ketolactam 104 possessing an acetoxy group a t C-4 with lead tetraacetate was tried, and the acetoxyketone 116 was solely obtained in 65% yield. Treatment of 116 with two equimoIar quantities of bromine, followed by heating with sodium acetate, provided the enol acetate 117 and the bromoacetate 118 in a 1 O : l ratio, but the yield of 117 was rather poor. However, the acetoxyketone 116 was brominated with pyridinium hydrobromide perbromide, and the reaction product 119 was heated with sodium acetate to give solely the enol acetate 117. Partial hydrolysis of the enol acetate function of 117 provided the a-diketone 120, which was brominated to give
@
: \
O H
o &
o&A(
. - f.
R N
. .
\O
AcO N
O \
N/-0
Me
67
I Me
114
Me
115
R = H
113 R = OAc
RN
. .
I
RO
RO
Me 104 R = H 116 R = OAc
Me
117
120
Me
118 R = AC 121 R = H
R = AC R =H
122 R = Me
Br\
0
&
OMe
7.
HASUBANAN ALKALOIDS
423
OMe
OMe
Br
Me0
. : . AcO N I
:fro
Me0
Me
Me 123
Me 124
119
OMe
OM0
?Me
Me0
Me0
Me0
Me
125 R = Me 127 R = H
Me
126 R = Me 128 R = H
Me 129
the bromoketone 121 in high yield. Methylation of 121 with diazomethane furnished compound 122, which was heated in an aqueous sulfuric acid according to the Hesses procedure to produce predominantly the p-diketone 123 together with the compound 124. The p-diketone 123 was methylated with diazomethane, and silica gel chromatographic separation gave 16-oxohasubanonine (125) and its isomer (126) from the earlier eluate in a 1 :1 ratio, and continued elution provided aknadilactam (127) and its isomer (128) in a 1:1 ratio. On the other hand, permanganate oxidation of hasubanonine produced optically active 16-oxohasubanonine (28,38),a sample of which was proved to be identical with that of the synthetic one (125) except in optical rotation. Since LAH reduction of 16-oxohasubanonine followed by oxidation with activated manganese dioxide regenerated hasubanonine, the synthesis of 16-oxohasubanonine is equivalent to the complete synthesis of hasubanonine (129) (38, 72).
424
C. METAPHANINE
The ketolactam 67 was also chosen as the starting material for the metaphanine synthesis. Since the introduction of an oxygen function a t the C-S position of 67 had been established during the synthesis of hasubanonine, the major problems are the stereoselective introduction of the C-10 hydroxyl group trans to the ethanamine bridge and the selective reduction of the lactam carbonyl group when both the lactam carbonyl and the hemiketal ring are present. Oxidation of 100 and 130 with chromic anhydride-acetic acid gave lo-0x0 compounds 131 and 132, respectively, but the yields were rather poor and irregular. The synthetic intermediate that had been utilized for the hasubanonine synthesis was converted to its ketal derivative 133.Chromic anhydride oxidation of 133 provided the 10-0x0 ketal lactam 134 in high yield. Hydrolysis of the acetoxyl groups of 134,followed by methylation with diazomethane, produced 10-0x0 compound 135.For the purpose of the hemiketal formation between C-8 and C-10, the relative configuration of the hydroxyl group derived from C-10 0x0 group must be trans to the ethanamine bridge. (The terms cis and trans in this section are
100 131
Me R = H, R =0
Me 130 132
Me 133 134
R R
= H, =0
R = H,
R =0
OR
Me
135
Me 136 R = H 143 R = Ac
Me 137
7.
OMe
HASUBANAN ALKALOIDS
425
OMo
OMe
Me
Me
141 142
Me
144
138
139 140
R R R
=H = AC = THP
R = Ao
R = THP
used to express the relative configuration of the C-10 hydroxyl group to the ethanamine bridge.) Reduction of 135 with various metal hydrides was tried, but the major product was the undesired cis C-10 hydroxyl compound 136, although the cis-trans ratio varied depending on solvents and metal hydrides used. Catalytic hydrogenation of the C-10 0x0 compounds 135 and 137 was unfruitful. Next, reduction of 135 with sodium in various alcohols was examined, and in this case, the yield of the trans isomer was superior to that of the cis isomer. However, the total yield was rather poor. Finally, reduction of 135 was successfully carred out by the Meerwein-Varley procedure to give the trans C-10 hydroxyl compound 138 in an excellent yield. After the hydroxyl group at C-10 of 138 was protected as an acetoxyl group or a pyranyl ether group, the acetate 139 or the pyranyl ether 140 was oxidized to produce the C-8 0x0 compound 141 or 142, Removal of the protected group afforded 16-oxometaphanine. Jones oxidation of the cis C-10 acetoxyl compound 143 gave the ketoacetate 144, which on treatment with aqueous sodium carbonate solution produced the C-10 0x0 compound 135. This rearrangement was assumed to be caused by an intramolecular 1,4 hydride shift from C-10 to C-S of compound 144. I n order to demonstrate this mechanism, 135 was converted to the deuterated cis C-10 hydroxyl compound 145, which gave the deuterated cis C-10 acetate 146 by acetylation. Jones oxidation of 146 gave the C-S 0x0 compound 147, which on treatment with aqueous sodium carbonate solution produced quantitatively the C-10 0x0 compound possessing deuterium at C-S with the ,l3 configuration, as indicated by the mechanism shown in 148. Thus, validity of the 1,4-hydride shift was verified, and the stereochemistry of the C-10 oxygen functions, which was based on the NMR spectral analyses, was chemically established.
426
"OR
I
Me 145 R = H 146 R = Ac Me
147
Me
148
"H
OTHP
Me
149 150 155
Me R =0 R =S
Me
151
.'H
HO N Me
152 153 154
Me
156
Me
157
Rl =
< : I ,
R, = 0
R l = 0, R, = S 1,= 0, R, = H,
The last step of this synthesis was reduction of the lactam carbonyl group of 150. Since this compound possesses a masked carbonyl group, the protection of the C-8 hemiketal hydroxyl group was examined, but all trials were unfruitful. Reduction of the pyranyl ether 142 with LAH and then oxidation of the resulting amine 151 did not lead to the desired (2-8 0x0 compound. Furthermore, Raney nickel reduction of the thio-
427
lactam 153 derived from the ketal lactam 152 gave the amino ketone 154, whereas a similar reduction of the thiolactam 155 derived from the compound 150 did not give the corresponding amino ketal. Finally, the lactam carbonyl group of 150 was converted to the imino ether by treatment with the Meerwein reagent, and reduction of this imino ether with NBH resulted in the amino ketal 156. Finally, hydrolysis of the ketal function provided metaphanine (157) (50, 51).
VI. Biosynthesis
Although the biosynthesis of the hasubanan alkaloids has not been fully established, hasubanonine (158) and protostephanine (159) have been shown by tracer experiments t o be biosynthesized from two different C-6-C-2 units (73). The nature of the building block of 158 and 159 was examined by feeding (2RS)-[2-14C]tyrosine (160), (2RS)-[2-14C]dopa (161), [2-14C]tyramine (162), and [2-14C]dopamine(163) to Stephaniajaponica plants. The results from these experiments showed that (a) both alkaloids are built from two different C,-C, units derivable from tyrosine; (b) one unit is a phenethylamine formed from both tyramine (162) and dopamine (163), and it generates ring C with its attached ethanamine residue for both natural products; and (c) dopa (161) affords only this same phenethylamine unit.
OMe
OMe
@
Me 158
Me
M e O "
159
OMe
160 161
R R
=H = OH
162 163
R =H
R = OH
HO 164 R = O H 165 R = OMe
R2
166 R, = OH, Rz = OMe 167 R 1 = OMe, F22 = OH
428
YASUO I N G R U S H I AND TOSHIRO I B U K A
168
HoDcc
R
169
R = H or OMe
R = O H or OBIe
Four I*C-labeled amines (164-167) and the putative isoquinoline intermediates were synt,hesized and tested in Stephania japonica plants. None of the isoquinolines was incorporated, but the amines 164 and 165 acted as precursors of 158 and 159. Degradation of hasubanonine unit had been built specifically proved that the trioxygenated C,-C, to form ring C and its ethanamine side chain. These findings show that the biosynthesis of hasubanonine (158) and protostephanine (159) in Xtephania japonica involves the first of the two alternatives above, and rejection by the plants of bases 166 and 167 indicates that further 0methylation is not the next step. By combining building block 165 with residue 168 or 169, a set of isoquinolines and bisphenethylamines can be designed to allow selection of the natural advanced intermediatefs) for the biosynthesis of 158 and 159 from the large number of structures that are possible (73).
REFERENCES
1. K. W. Bentley, in The Alkaloids (R. H. F. Manske, ed.), Vol. XIII, pp. 131-145.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Academic Press, New York, 1971. Chemical Abstracts, 8th Collective Index, Index Guide, 3420, 1041G (1972). H. L. de W a d , B. J. Prinsloo, and R. R. Arndt, Tet. Lett. 6169 (1966). H. L. de Wall and E. Weideman, Tydskr. Natuurwet. 2, 12 (1967). S. M. Kupchan, A. J. Liepa, and T. Fujita, J . Org. Chem. 38, 151 (1973). S. M. Kupchan, M. I. Suffness, R. J. McClure, and G . A. Sim, J . Am. Chem. SOC. 92, 5756 (1970). M. Tomita and M. Kozuka, Tet. Lett. 6229 (1966). I. I. Fadeeva, T. N. Ilinskaya, BI. E. Perelson, and A. D. Kuzovkov, K h i m . P r i r . Soedin, 7 , 784 (1971); C A 76, 1 4 1 1 0 8 ~ (1972). T. N. Ilinskaya, M. E. Perelson, I. I . Fadeeva, D. A. Fesenko, and 0. N. Tolkachev, K h i m . Prir. Soedin. 8, 129 (1972); C A 77, 98719d (1972). B. K. Mom, B. Bhaduri, D. K. Basu, J. Kunitomo, Y. Okamoto, E. Yuge, Y. Nagai, and T. Ibuka, Tetrahedron 26, 427 (1970). S. M. Kupchan, BI. I. Suffness, D. N. J. White, A. T. RlcPhail, and G. A. Sim, J. Org. Chem. 33, 4529 (1968). B. K . Mom and D. K. Basu, I n d i a n J . Chem. 5 , 281 (1967). T. N. Ilinskaya, D. A. Fesenko, I. I. Fadeeva, M. E. Perelson, and 0. N. Tolkachev, hhim. P r i r .Soedin. 7, 180 (1971); C A 75, 36408b (1971).
7.
HASURANAN ALKALOIDS
429
14. I . I . Fadeeva, D. A. Fesenko, T. N. Ilinskaya, M. E. Perelson, and 0. N. Tolkachev, Khim. Prir. Soedin. 7, 455 (1971); C A 75, 49369q (1971). 15. I . I. Fadeeva, T. N. Ilinskaya, M. E. Perelson, and A. D. Kuzovkov, Khim. Prir. Soedin. 5, 492 (1969); CA 74, 1035713 (1971). 16. D. A. Fesenko, I. I. Fadeeva, T. N. Ilinskaya, M. E. Perelson, and 0. N. Tolkachev, Khim. Prir. Soedin. 7, 158 (1971); CA 75, 49369q (1971). 17. I. I. Fadeeva, M. E. Perelson, T. N. Ilinskaya, and A. D. Kuzovkov, Farmatsiya (Moscow)19, 28 (1970); C A 73, 25717j (1970); I. I. Fadeeva, A. D. Kuzovkov, and T. N. Ilinskaya, Khim. Prir. Soedin. 3, 106 (1967); C A 67, 43966 (1967). 18. I. I. Fadeeva, M. E. Perelson, 0. N. Tolkachev, T. N. Ilinskaya, and D. A. Fesenko, Khim. Prir. Soedin. 8, 130 (1972); CA 77, 72561w (1972). 19. S. M. Kupchan and M. I. Suffness, Tet. Lett. 4975 (1970). 20. M. Tomita, T. Ibuka, Y. Inubushi, and K. Takeda, Tet. Lett. 3605 (1964). 21. M. Tomita, T. Ibuka, Y. Inubushi, and K. Takeda, Chem. Pharm. Bull. 13, 695, 705 (1965). 22. H. Kondo and T. Sanada, J . Pharm. Soc. Jpn. 45, 1034 (1924); C A 19, 1709 (1925). 23. H. Kondoand T. Watanabe, J . Pharm. Soc. J p n . 58,268 (1938); CA 32, 54035 (1938). 24. K. Takeda, Annu. Rep. f T S U U Lab. 11, 6 (1960); CA 55, 26005d (1961). Jpn. 85, 579 (1965); CA 63, 116296 (1965). 25. T. Ibuka, J. Pharm. SOC. 26. M. Tomita, T. Ibuka, and Y. Inubushi, Tet. Lett. 3167 (1964). Jpn. 87, 381 (1967); CA 27. M. Tomita, Y. Inubushi, and T. Ibuka, J . Pharm. SOC. 67, 73723f (1967). 28. Y. Watanabe, M. Matsui, and M. Uchida, Phytochemistry 14, 2695 (1975). 29. M. Tomita, Y. Watanabe, and K. Okui, J . Pharm. SOC. Jpn. 76, 856 (1956); C A 50, 14789f (1956). 30. Y. Watanabe, M. Matsui, and K. Ido, J . Pharm. SOC. Jpn. 85, 584 (1965); C A 63, 1 1 6 3 0 ~ (1965). 31. T. Ibuka and M. Kitano, Chem. Pharm. Bull. 15, 1939 (1967). 32. M. Tomita, T. Ibuka, Y . Inubushi, Y. Watanabe, and M. Matsui, Tet. Lett. 2937 (1964); Chem. Pharm. Bull. 13, 538 (1965). 5 1 3 % .87, 1014 33. T. Ibuka, M. Kitano, Y. Watanabe, and M. Matsui, J . Pharm. SOC. (1967); C A 68, 3053j (1968). 34. H. Kondo and M. Satomi, Annu. Rep. I T S U U Lab. 8 , 6 (1957);C A 51, l7956i (1957). 35. Y. Watanahe and H. Matsumura, J . Phurm. Soc. Jpn. 83, 991 (1963); C A 60,4201d (1964). 36. T. Ibuka and M. Kitano, Chem. Pharm. Bull. 15, 1809 (1967). C 2313 (1966). 37. D. H. It. Barton, G. W. Kirby, and A. Wiechers, J . Chem. SOC. 38. T. Ibuka, K. Tanaka, and Y. Inubushi, Chem. Pharm. Bull. 22, 782 (1974). 39. A. R. Battersby, S. R. Ruchirawat, T. Stanton, and C. W. Thornber, unpublished work: C. W. Thornber, Ph.ytochemistry 9, 157 (1970). 40. M. Blatsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Tet. Lett. 4263 (1973). 41. M. Matsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Chem. Pharm. Bull. 23, 1323 (1975). 42. J. Kunitomo, Y. Okamoto, E. Yuge, and Y. Nagai, T e t . Lett. 3287 (1969). 43. J. Kunitomo, Y. Okamoto, E. Yuge, and Y . Nagai, J . Pharm. SOC. Jpn. 89, 1691 (1969); CA 71, 113125d (1969). 44. 31. Tornita, A. Kato, and T. Ibuka, Tet. Lett. 1019 (1965). 45. 11. Tomita, A. Kato, and T. Ibuka, Mass Spectrose. ( T o k y o ) 13, 115 (1965). 4 6 . %I. Tomita, T. Ibuka, and M. Kitano, Tet. Lett. 6233 (1966). 47. T. Ibuka and 31. Kitano, Chem. Pharm. Bull. 15, 1944 (1967).
430
48. K. W. Bentley, i n The Chemistry of the Morphine Alkaloids, p. 358. Oxford Univ. Press (Clarendon), London and New York, 1952. 49. D. Ginsburg, i n The Opium Alkaloids, pp. 13-17. Wiley (Interscience), New York, 1962. 50. T. Ibuka, K. Tanaka, and Y. Inubushi, Tet. Lett. 1393 (1972). 51. T. Ibuka, K. Tanaka, and Y. Inubushi, Chem. Pharm. Bull. 22, 907 (1974). Chim. Fr. 586 (1963). 52. T. Riill, Bull. SOC. 53. T. Riill, Bull. SOC. Chim. Fr. 2189 (1963). 54. K. Abe, Y. Nakamura, M. Onda, and S. Okuda, Tetrahedron 27, 4495 (1971). 55. S. Okuda, K. Abe, S. Yamaguchi, and T. Ibuka, Chem. Pharm. Bull. 16, 370 (1968). 56. M. Tomita, M. Kitano, and T. Ibuka, Tet. Lett. 3391 (1968). 57. Y. Inubushi, T. Ibuka, and M. Kitano, Tet. Lett. 1611 (1969). 58. Y. Inubushi, M. Kitano, and T. Ibuka, Chem. Pharm. Bull. 19, 1820 (1971). 59. D. A. Evans, Tet. Lett. 1573 (1969). 60. D. A. Evans, C. A. Bryan, and G. M. Wahl, J . Org. Chem. 35, 4122 (1970). 61. S. L. Keely, Jr., A. J. Martinez, and F. C. Tahk, Tet. Lett. 2763 (1969). 62. S. L. Keely, Jr., A. J. Martinez, and F. C. Tahk, Tetrahedron 26, 4729 (1970). 63. S. L. Keely, Jr., and F. C. Tahk, J . Am. Chem. SOC. 90, 5584 (1968). 64. R. V. Stevens and M. P. Wentland, J. Am. Chem. SOC. 90, 5580 (1968). 65. T. J. Curphey and H. L. Kim, Tet. Lett. 1441 (1968). 66. D. A. Evans, C. A. Bryan, and C. L. Sims, J . Am. Chem. SOC. 94, 2891 (1972). 67. I. Monkovic and T. T. Conway, U.S. Patent 3,775,414 (1973). 68. T. Kametani, T. Kobari, and K. Fukumoto, J . Chem. SOC., Chem. Commun. 288 (1972) 69. R. E. Bowman, Chem. I d . (London) 1077 (1969). 70. K. E. Pfitzer and J. G. Mofatt, J . Am. Chem. SOC. 87, 5661, 5670 (1965). 71. T. Kametani, H. Nemoto, T. Kobari, K. Shishido, and K. Fukumoto, Chem. I d . (London) 538 (1972). 72. T. Ibuka, K. Tanaka, and Y. Inubushi, Tet. Lett. 4811 (1970). 73. A. R. Battersby, R. C. F. Jones, R. Kazlauskas, C. Poupat, C. W. Thornber, S. Ruchirawat, and J. Staunton, J . Chem. SOC., Chem. Commun. 773 (1974). 74. I. Monkovic, T. T. Conway, H. Wong, Y. G. Perron, I. J. Pachter, and B. Belleau, J. Am. Chem. SOC. 95, 7910 (1973). 75. S. Shiotani and T. Kometani, Tet. Lett. 767 (1976).
-CHAPTER
8 -
THE MONOTERPENE ALKALOIDS

GEOFFREY A . CORDELL
University of Illilzois Chicago. Illinois
I. Introduction ........................................................ I1. Isolation and Structure Elucidation of the Monoterpene Alkaloids .........
A . Skytanthine ..................................................... B . Tecomine and Tecostanine ........................................ C. Tecostidine ...................................................... D . Hydroxy- and Dehydroskytanthines ................................ E . Actinidine ....................................................... F. The Quaternary Alkaloids of Valeriana oflcinalis .................... G . Boschniakine (Indicaine) and Boschniakinic Acid (Plantagonine) . . . . . . . H . N.Normethy1skytanthine .......................................... I. 4-Noractinidine .................................................. J Cantleytine ...................................................... K . Venoterpine (Gentialutine) and Isogentialutine ....................... L Leptorhabine .................................................... M Bakankoside ..................................................... N . Gentianine ...................................................... 0. Fontaphilline .................................................... P. Gentianadine .................................................... Q. Gentianidine ..................................................... R Gentianamine ................................................... S. Gentioflavine .................................................... T. Gentiocrucine, Enicoflavine, and Gentianaine ........................ U . Jasminine ....................................... ............. V . Gentiatibetine and Oliveridine ..................... ............. w .Unnamed Alkaloids from Gentiana tibetica .......................
. . .
432 432 432 435 437 438 440 442 443 445 446 446 448 450 450 452 454 455 456 457 457 458 462 463
d Pediculinine ...................................... . Pedicularine, Pedicularidine, and Pediculine ......................... 1 1 1 - Biosynthesis and Biogenesis of the Monoterpene Alkaloids ................ A. Skytanthines .................................................... B . Alkaloids of Tecoma stam ......................................... c. Actinidine and the V a l e k n a Alkaloids ............................. D. Gentianine ...................................................... E . Gentioflavine .................................................... F. Biogenesis ............ ...................................
..............................................
466 467 470 470 487 487 488 489 492
432
GEOFFREY A. CORDELL
IV. Pharmacology of the Monoterpene Alkaloids. ........................... A. Actinidine ....................................................... B. Tecomine and Tecostanine ........................................ C. Gentianadine .................................................... D. Gentianine ...................................................... E. Skytanthine .....................................................
F. Summary ....................................................... References .........................................................
499 500 500 500 500 502 502 502
I. Introduction
Original thoughts on the biogenesis of the monoterpene alkaloids, in particular gentianine (l),centered on the prephenic acid hypothesis. When Thomas ( 2 ) and Wenkert ( 3 )introduced their theories on indole alkaloid biosynthesis from an iridoid precursor, it became clear that the other alkaloids could also be derived from the iridoids. The alkaloids, rather than condensing with tryptamine/tryptophan with subsequent reaction, would condense with ammonia and give a series of alkaloids containing a C,, unit. Since these early days, a substantial number of alkaloids formed in this manner have been isolated. As further compounds of this type were isolated, two distinct types became apparent, the iridoids and those with a cleaved cyclopentane ring, the secoiridoids. The organization of this chapter is based on this distinction as applied to the monoterpene alkaloids. Thus, the alkaloids derived from a secoiridoid are treated later. This approach is continued in the section dealing with the biosynthesis and biogenesis. Original interest in many of the plants from which these alkaloids have been isolated was in most cases based on experimental or folkloric experience with the crude drug. This data and subsequent work on the pharmacology of the alkaloids isolated from these drugs concludes this chapter. A number of reviews of this general area are available (4-18).
11. IsoIation and Structure Elucidation of the Monoterpene Alkaloids
A, SKYTANTHINE
Coincidentally, in 1961, two groups (19-22) isolated skytanthine from the Chilean shrub Skytanthus acutus (Apocynaceae)and a year later a third isolation was reported (23).Degradation of skytanthine demonstrated the bicyclic nature and the location of one of the methyl groups
8. MONOTERPENE ALKALOIDS
433
and permitted formulation 1 in which the methyl group on the fivemembered ring could not be placed ( 2 0 , 2 2 ) . One of the first applications of NMR spectroscopy in the area of natural product structure elucidation was used successfully for skytanthine ( 2 0 , 2 2 ) .The NMR spectrum of the dehydrogenation product established the presence of thirteen protons, and together with the analytical data for the picrate, supported a molecular formula of C1,H,,N. Five lines of a sextet were visible in the NMR spectrum at 6 3.2 ppm. Thus, the dehydrogenation product could be represented as either 2 or 3,and the latter was favored on biogenetic grounds. Compound 3 was very similar to the actinidine isolated by Sakan (24). Direct comparison of the natural actinidine and the dehydrogenation product of skytanthine confirmed their identity. Skytanthine, therefore, has structure 4, for which no stereochemistry could be assigned.
CH3
1
A different approach was used by the Italian workers ( 1 9 , 2 1 ) . Analytical data indicated two C-methyl and one N-methyl groups and a molecular formula C,,H,,N. Dehydrogenation afforded a substituted pyridine, which must also be joined to a five-membered ring. On this basis, it was suggested that skytanthine was a monoterpene alkaloid, and three structures were proposed in accordance with the isoprene rule. Once again, the dehydrogenation product was established as actinidine. Differences in the physical constants of the materials isolated by the Italian group (19, 21) and by Appel and Miiller (23)led to a more careful examination of the problem.
434
GEOFFREY A. CORDELL
Gas chromatography of skytanthine indicated the presence of four peaks (25).A number of stereochemical possibilities are available for skytanthine, and four of these were synthesized (25) from the a-,/?-, y-, and 6-nepetalinic acids (26) by LAH reduction, ditosylation, and cyclization with excess methylamine. I n this way the pure skytanthines 5 , 6 , 7 , and 8 were obtained having [.ID and picrate properties as shown (25). Similarly, the Italian group also synthesized a-, /?-, y-, and S-skytanthine (27, 28). Preparative gas chromatography demonstrated that a-, /?-, and &skytanthine were present in the original skytanthine, the /? isomer 6 predominating (25). Later, gas chromatography (29, 30) and thin-layer chromatography (31, 32) were used to demonstrate that the percentages of /3-, a-,and &isomers were 70, 20, and 3oJ, respectively.
CH,
5
a
ra1D
CH,
6
+ 79"
120C
+ 16'
135C
Picrate mp
CH3
7
I
CH3 8 6
9" 139C
+ 59"
162C
A study of the Hofmann elimination of a-,/?-, y-, and 6-skytanthines (30) unearthed pronounced differences in product composition. These subtle differences were correlated with the stereochemistry of the starting materials, resulting in differences in the elimination versus regeneration of tertiary amine reactions. Careful isolation work demonstrated that both the a- and /?-Skytanthines were absent from freshly collected roots of Skytanthus acutus (33,34)but were present in the dried branches.
8. MONOTERPENE
ALKALOIDS
435
Aspects of the early work on Skytanthus alkaloids have been summarized ( 4 , 6 ) . Oxidation of /3-skytanthine (6) with 30y0hydrogen peroxide afforded the N-oxide (9) and this process was reversed with Zn/dilute HC1 (33,35)./3-Skytanthine N-oxide was also obtained from the leaves (33) and roots (35) of S. acutus. The precursors of a- and /3-skytanthine in S. acutus are still unknown, but it has been suggested that the N-oxide (9) is the natural product, which is reduced during steam distillation by the sugars present. Further investigation of S. acutus by Gross and co-workers (36) afforded a base, which by its mass spectrum was shown to be a fully saturated skytanthine derivative. The characteristic ions a t m/e 84 due to 10 as well as smaller fragments a t m/e 58, 11, the base peak, and mle 44, 12, were observed in the mass spectrum. The base formed a picrate (mp 144-146C) and a methiodide (mp 300302C). This information together with the low optical rotation + loo)indicated that the free base was &skytanthine (8) (36).
(@,cH3
CH3
73
CHZN ,CH3 N@
Y\o@
CH3
9
C H ,
N@ \CH,
10
CH3
11
12
B. TECOMINE (13) AND TECOSTANINE (16)
Tecoma stuns (Bignoniaceae) and a number of other Tecoma species are used in Mexico by the natives for the control of diabetes (37, 38). The two alkaloids tecomine (tecomaine) and tecostanine have been isolated and characterized and are apparently responsible for hypoglycemic activity of the plant (see Section IV).
436
GEOFFREY A. CORDELL
Tecomine was isolated by Hammouda and Motawi in 1959 (39) by chromatography of the alkaloid fraction. Little structure work was attempted except for the demonstration of the presence of a carbonyl group and the formation of several derivatives. Subsequently, Jones and co-workers (40, 41) obtained an unstable liquid alkaloid from T. stuns. The alkaloid formed both a picrate and a methiodide, and the UV and I R spectra indicated the presence of an cc$-unsaturated cyclopentenone. Only one aromatic proton was present in the NMR spectrum together with two three-proton doublets and an N-methyl group. Reduction in acetic acid and subsequent Huang-Minlon reduction gave a mixture of three bases which upon Pd-C dehydrogenation gave actinidine (3). The gross structure of tecomanine was therefore established as 13 (40, 41). Catalytic reduction in ethanol added one molar equivalent of hydrogen, and the major dihydro derivative was obtained by recrystallization of the picrate. Huang-Minlon reduction gave a single base, which again was characterized as the picrate. Comparison with the four known synthetic (25) skytanthine picrates indicated that the derivative was new. Tecomanine and tecomine were subsequently shown to be identical by direct comparison of their I R spectra and mixed melting point determination of their picrates ( 4 2 ) .It remains to determine the stereochemistry of tecomine. A study of the stability of tecomine indicated that degradation is pH dependent, being most rapid a t high pH, and that antioxidants are beneficial in preventing decomposition ( 4 3 ) . Tecostanine, a crystalline base, was also obtained by Hammouda (42), and its structure was subsequently established in collaboration with Le Men and Plat ( 4 4 ) .The I R spectrum indicated the presence of an alcohol function, and this was confirmed by the facile acetylation to give a monoacetate derivative ( 4 2 ) .The oxygen atom was removed by tosylation and LAH reduction. The resulting deoxy base was dehydrogenated (Pd-C), and the product was shown to be identical with actinidine (3).The deoxy base therefore has structure 4, but again, the deoxy compound was not identical with any of the synthetic skytanthine isomers ( 2 5 ) or the deoxy derivative of tecomine (40, 41). Tecostanine is therefore a hydroxyskytanthine derivative, and the nature of the hydroxyl function was readily determined to be a primary alcoholfrom the NMR spectrum (broad two-proton doublet a t 3.56 ppm). A decision on the position of the hydroxyl function was made after careful examination of the mass spectrum ( 4 4 ) . Fragment ions were observed at m/e 100, 58 (11),and 44 (12).The ion a t m/e 100 was shifted to m/e 84 in deoxytecostanine and to m/e 85 when LAD was used in place of LAH in the formation of deoxytecostanine. These data are in
437
H0cHa??cH3
CH3 I
16
accord with a fragmentation such as 14 to give the ion 15 as shown in Scheme 1. The primary hydroxyl function is therefore located as shown in 16 ( 4 4 ) ,and it remains to determine the stereochemistry of tecostanine.
C. TECOSTIDINE
A further alkaloid of the actinidine type has also been isolated from T .stuns ( 4 5 ) .From the mother liquor after crystallization of tecostanine,
an unstable base was obtained that gave a crystalline picrate and showed a small negative rotation. The UV spectrum indicated the presence of a 3,4,5-substituted pyridine, and the IR spectrum showed the presence of an alcohol function. The base could not be reduced catalytically, and the presence of an actinidine-type structure was suggested. Thirteen protons could be observed in the NMR spectrum and this, together with an observed molecular ion of m/e 163, suggested a molecular formula of C,,H,,NO. The NMR spectrum proved definitive in determining the structure, or two singlets were observed at 6 8.22 and 8.27 ppm corresponding to the 2- and 6-protons of the pyridine ring and a three-proton doublet at 6 1.27 ppm. The methyl group is therefore in the cyclopentane ring and the hydroxyl group (singlet for two protons at 6 4.65 ppm) on the carbon attached to the pyridine nucleus. Tecostidine therefore has structure 17 (45).
438
GEOFFREY A. CORDELL
From Pedicularis rhinantoides, Abdusamatov and Yunusov (46) isolated a base having a molecular formula Cl,,Hl,NO and showing hydroxyl absorption in the IR spectrum. Oxidation of the base with alkaline permanganate afforded a carboxylic acid that was shown to be identical with boschniakinic acid (18) ( 4 7 ) . The base from P.rhinantoides therefore has the gross structure 17, but since the DI.[ of this base was + 59, it is the optical antipode (19) of the material from T.stuns.
17
C H 1 O . i p
go
18
CH,
CH3
20
IS
Confirmation of the structure of tecostidine was obtained by synthesis of the d isomer (19) from d-pulegone (20) ( 4 8 , 4 9 )using a route similar to that used for actinidine (50, 51) (see below, Section E, Scheme 2).
D. HYDROXYAND DEHYDROSKYTANTHINES
In 1961 Appel and Muller isolated from S. acutus a crystalline nonvolatile alkaloid (23) and suggested that it was a hydroxy derivative of skytanthine. Subsequently, this compound, alkaloid D, was subjected to more careful analysis (52). The IR spectrum confirmed the presence of a hydroxyl group, and the NMR spectrum indicated that this group was probably tertiary and attached a t the site of one of the methyl groups (three-proton singlet a t 6 1.24 ppm). Also observed were a secondary methyl group (three-proton doublet a t 6 0.85 ppm) and an N-methyl group (three-proton singlet a t 6 2.3 ppm). On this basis, structures 21 and 22 were proposed for alkaloid D (52). In 1967, alkaloid D was reisolated from S. acutus together with a second isomeric alkaloid (53).The NMR spectrum of this alkaloid was
8.
MONOTERPENE ALKALOIDS
439
similar to that of alkaloid D, showing methyl singlets a t 6 2.18 ppm for the N-methyl group and at 6 1.12 ppm for the methyl group of the tertiary alcohol. Thus, alkaloid D, renamed hydroxyskytanthine I, and the isomer hydroxyskytanthine 11, had structures 21 and 22 or the reverse (53).A decision on these structure assignments was made on the basis of NMR and mass spectral analysis. I n the NMR spectrum of hydroxyskytanthine I, the 3a- and 3pprotons were readily discerned to be doublets, whereas in hydroxyskytanthine I1 both doublets are further coupled. Hydroxyskytanthine I, therefore, has the structure 22 (53). The mass spectrum of hydroxyskytanthine I1 (21) showed ions a t mle 84 and mle 110 ascribed to the species 15 (R = H) and 23. These ions were not observed in the mass spectrum of hydroxyskytanthine I. As well as the hydroxyskytanthines I and I1 isolated from Skytanthus acutus, two additional hydroxyskytanthines have been isolated from Tecoma stuns (41). Both bases showed no UV absorption and had
I
CH, 21
CH, 22 23
I
CH,
m/e 110
molecular formulas of C,,H,,NO. The oxygen function was traced to a hydroxyl group from the IR spectrum. Two C-methyl doublets and an N-methyl group were observed in the NMR spectrum, and in the absence of low-field methine or methylene protons, the hydroxyl function must be tertiary. This data and consideration of the mass spectrum led to structures 24 and 25 for the two hydroxyskytanthines. A distinction between these two possible structures was made on the basis of an examination of the IR spectrum. I n the spectrum of the
440
GEOFFREY A. CORDELL
cH3fl czQfl:3
,+'
C H 3 f l H O 'H CH3
base mp 82-94'C, intramolecular hydrogen bonding was observed, suggesting structure 25 for this compound and structure 24 for the base mp 91-99"C (41). Two other skytanthine-type alkaloids have been isolated and shown to be dehydroskytanthines. Casinovi and co-workers (29,52)obtained a base by preparative gas chromatography and showed that it had the molecular formula C,,H,,N. The NMR spectrum indicated the presence of an olefinic methyl group (singlet at 6 1.50 ppm integrating for three protons), and reduction with PtO, in acetic acid afforded 6 skytanthine having the configuration 8. On this basis, the structures 26 and 27 were suggested for this dehydroskytanthine (29, 52). Treatment of hydroxyskytanthine I (alkaloid D) with thionyl chloride gave dehydroskytanthine identical with that obtained previously (52).The elucidation of the structure of hydroxyskytanthine I as 22 permitted deduction of the structure of dehydroskytanthine to be 27 (53).
I
CH3
26
CH,
27
CH3
28
I n 1973, Gross and co-workers (36)obtained another alkaloid, which by the molecular ion a t mle 165 suggested that it was a dehydroskytanthine. The base formed a picrate and a methiodide. Catalytic hydrogenation (5y0Pd-C) gave a dihydro derivative identical with a-skytanthine (8).The NMR spectrum indicated the presence of two secondary methyl groups and only one oIefinic proton ( 6 5.5 ppm). Since the mass spectrum showed the presence of ions a t mle 58 and 44, the double bond must be a t the A5 position, and this dehydroskyanthine therefore has the structure 18 (36).
E. ACTINIDINE (37)
Actinidine, one of the simplest monoterpenoid alkaloids, was fist isolated from Actinidia polygama (24, 54, 55) and subsequently from A . arguta (56),Valeriana oflcinalis (57, 58), Tecoma radicans (56),and T . fulva (59). Co-occurring with actinidine in A . polygama was a nonnitrogenous neutral substance, metatabilactone (24, 55) (from the
441
Japanese colloquial name for A . polygama, matatabi). Hydrolysis of matatabilactone gave a hydroxy acid, which upon permanganate oxidation afforded two isomeric dicarboxylic acids identical with the nepetalinic acids (26) obtained from nepetalactone. On this basis, structure 29 was suggested for matatabilactone ( 2 4 , 5 5 ) .
iG
CH3 0 CH3
29
COaH
CH3
. C J + ;
+ o
CH3
30
31
Permanganate oxidation of actinidine gave, among other products, 5-methylpyridine-3,4-dicarboxylic acid, and on the basis of biogenetic considerations, the probable structure 3 was suggested for actinidine (24). Confirmation of this gross structural assignment was obtained by synthesis. Nepetalinic acid imide (31) on treatment with PCl, a t 100C afforded a 2,6-dichloropyridine, which was dehalogenated with Pd-C to give actinidine (24, 60). I n 1960, Sakan and co-workers published a series of papers describing fully their work on actinidine (51, 55, 60-62). Synthetic dl-actinidine was prepared in five steps from 32 and resolved with dibenzoyl-1-tartaric acid (62) (Scheme 2). The absolute configuration of natural actinidine
7H3
NaCN/H,SOI 2. SnC1,lpyridine
1.
7H3
0
1. 2.
POCID, 200C
PdCI,/KOAc
3. HCI, A
+ 3
q C O z C 2 H 6 CH3 32 CH3
35
OH
442
GEOFFREY A. CORDELL
was also determined by synthesis (50,51) (Scheme 2 ) . (+)-Pulegone (20) was converted t o methyl pulegenate (33), which was ozonized, and the ketone was treated with the potassium salt of ethyl cyanoacetate to give 34, the sodium salt of which on treatment with methyl iodide followed by hydrolysis gave optically active 35, which was transformed into d-actinidine (36)as before. Natural actinidine, therefore, has the I-configuration and the structure 37. A number of monoterpenoid alkaloids have been correlated with actinidine. These include boschniakine (63),tecomine (40), skytanthine (ZO), tecostidine (as),and a n unnamed Valerianu alkaloid (64, 65). The chemistry of Actinidia polygama has been reviewed (9, 66).
36
37
F. THEQUATERNARY ALKALOIDS OF Valerianu oficinalis (38 and 39)

I n addition to actinidine (57, 58), two other alkaloids in this series have been isolated from the roots of Valeriana oficianalis (57, 64, 65). Both alkaloids are quaternary, and because of their close similarity, they will be discussed together. One of these alkaloids showed a molecular formula of C18H2,NOCI and the other C18H2,N02C1, indicating the presence of a hydroxyl group in the second isolate. The first alkaloid isolated (64, 65) showed strong hydrogen bonding in the IR spectrum in addition to characteristic aromatic bonds indicating the presence of a para-substituted aromatic ring. Nn carbonyl bands were observed. The UV spectrum also indicated the presence of
cH3fl
CH,R
38 39
R = H R=OH
8.
443
both pyridine and phenolic chromophores, the latter shifting from 222 and 267 nm to 242 and 292 nm on addition of alkali. Essentially identical data were observed for the second alkaloid (65),but in the IR spectrum, further absorptions at 3200 and 1047 cm-l confirmed the presence of an additional nonphenolic hydroxyl group. The NMR spectra of the alkaloids and their derivatives was particularly revealing. Two singlets a t 6 8.90 and 8.83 ppm were ascribed to the 2,6 protons on a pyridine nucleus and two doublets (J = 8.8 Hz) a t 6 7.04 and 6.73 pprn to a para-substituted aromatic nucleus. Both compounds showed a complex four-proton multiplet in the region 6 4.70 ppm, which could be ascribed to two low-field methylene groups, and each compound showed a three-proton doublet a t about 6 1.23 ppm, indicative ofa secondary methyl. However, whereas the first (and major) alkaloid showed a three-proton singlet a t 6 2.34 pprn for an aromatic methyl group, the second compound showed the presence of a twoproton singlet a t 6 4.68 ppm, indicating that the second hydroxyl group was on the aromatic methyl (65). Strong peaks in the mass spectrum of the trifluoroacetate of the major alkaloid were observed at m/e 268 (parent pyridinium species) 147, 132 (base peak), and 120. It was clear that cleavage of the molecule tQgive m/e 147 and 120 had occurred, the latter being the phenolic part and the former the pyridine nucleus (64).I n the mass spectrum of the minor alkaloid, the pyridine fragment was shifted to m/e 163 and the base peak to m/e 148 (65). Pyrolysis (64, 65) of the major alkaloid and isolation of the base as - ) actinidine (37). On this the picrate indicated an identity with (8)-( basis, structure 38 was proposed for the major alkaloid and structure 39 for the minor alkaloid. Treatment of (IS)-( - ) actinidine (37) with p-hydroxyphenylethyl bromide and formation of the picrate confirmed structure 38 for the major alkaloid (65).The enantiomer of 38 has also been synthesized (57).
G. BOSCHNIAKINE (INDICAINE) (44) AND BOSCHNIAKINIC ACID (PLANTAGONINE) (IS)

Indicaine was first isolated in 1952 from Plantago indica (67). The Russian workers suggested a molecular formula of C,,H,,NO. Subsequently, indicaine was isolated from Plantago ramosa (68)and Pedicularis olgae (69-71). Preliminary structure work demonstrated that indicaine was an amino aldehyde. The compound gave a picrate
444
GEOFFREY A. CORDELL
(mp 151-153OC) (67, 68) and could be oxidized with silver oxide or nitric acid to an acid (68). This acid, called plantagonine, was also obtained as a natural product, initially from P. ramosa (68) and subsequently from P. olqae (69, 70). On the basis of degradative and spectral evidence, structure 40 was proposed for plantagonine (70) and by inference 44 for indicaine. The UV spectrum was characteristic of a pyridine and supported the presence of a methyl group at a secondary carbon atom. Exhaustive KMnO, oxidation gave an amino acid, which was decarboxylated to nicotinic acid on heating. The amino acid was identified as pyridine-3, 5-dicarboxylic acid (42) by comparison with an authentic sample (70). I n 1968, the structures for plantagonine and indicaine were revised when it was demonstrated that alkali permanganate oxidation of plantagonine gave pyridine-3,4,5-tricarboxylic acid (43), and therefore to have structures 18 and 44, respectively (47).Independently, Torssell arrived a t the same structural conclusions for plantagonine and indicaine based on examination of their spectral properties (71) and by comparison with the ethyl ester of plantagonine (45), which had been prepared independently (48). Also isolated at this time was an alkaloid, boschniakaine, from Boschniakia rossica (72).This base formed a picrate and a carbazone, thereby indicating that it was an amino aldehyde, and this was confirmed by the I R spectrum. Also isolated was an acid that could be derived from the aldehyde by silver oxide oxidation. The structures 18 and 44 were assigned to these compounds (72).I n order t o confirm the
40
41
R = CO,H R=CHO
42
43
R = H R = COpH
I8
44 45
R = CO,H R=CHO R = CO,C.H,
structure assignments and determine the absolute stereochemistry, boschniakine (dl and d ) was synthesized by a route analogous to that used for the synthesis of actinidine ( 5 0 , 5 1 )(Scheme 3 ) . The product was and therefore belongs to the identical with the natural boschniakine (44) opposite antipodal series than the other actinidine-type alkaloids. Boschniakine has also been isolated from Tecoma stuns ( 4 4 , where it co-occurs with a d-actinidine derivative, and from T. radieans (56).
8.
445
1.
40
Oa/CCI*
QOH
P 1. POCla
2.
2. K 8 CH,CO.C.HS
PdC12IKOAc
CN
, NH.
CN
QCH,
SnCl./HCl
44
CN
SCHEME 3
I n 1973, Gross and co-workers (73) demonstrated that in spite of apparent differences in the physical properties of boschniakine and indicaine, they were in fact identical. I n particular, recrystallization of the picrate from ethanol gave a product of mp 126OC. Plantagonine and boschniakinic acid are also probably identical, but no direct comparison has been made. Isolated from P . olgae as a picrate (mp 125-127C) was a quaternary alkaloid analyzing for Cl2H1,NO (74).The I R spectrum indicated the presence of an aldehyde, and this was confirmed by the NMR spectrum (singlet a t 6 3.49 ppm and a six-proton multiplet at 6 1.25 ppm, suggesting the presence of a N-ethyl and a methyl group). Oxidation of
+
CZHS
46
indicainine, as the compound was named, gave boschniakinic acid (18). Indicsinine was therefore assigned the structure 46. The correctness of this structure has been questioned (73).
H . N-NORMETHY LSKYTANTHINE (47)

A further alkaloid from Tecoma stuns analyzed for C,,HI9N (41).The IR spectrum indicated the presence of NH, and no N-methyl group was observed in the NMR. Dehydrogenation afforded actinidine (3),
446
GEOFFREY A. CORDELL
identified as its picrate. The base was therefore identified as Nnormethylskytanthine (47). N-Methylation afforded a skytanthine derivative, which was similar to the skytanthine derived from tecostanine ( 4 4 ) .The stereochemistry of N-normethylskytanthine remains to be determined.
CH3
47
I.
4-NORACTINIDINE
(48)
From Tecoma stuns, Dickinson and Jones (41) isolated an alkaloid C9H,,N as the picrate. The UV spectrum a t 259.5 and 267 nm indicated a 3,4-disubstituted pyridine, and this assignment was confirmed by the
NMR spectrum, which showed three aromatic protons. A three-proton doublet was observed 6 1.6 ppm, and five other protons were observed
as multiplets, including three benzylic protons in the 6 3.2-3.8 ppm region. The structure 4-noractinidine (48), with the d configuration, was assigned to this compound (41). Its picrate showed no melting point depression with a synthetic sample of 8-epi-4-noractinidine picrate derived from asperuloside (75).
48
J . CANTLEYINE (50) From an unidentified Jasminum species (designated NGF 29929) Johns and co-workers (76)isolated a new pyridine derivative. The new alkaloid had an elemental composition of C,,H,,NO, by analysis, and this was supported by a molecular ion at mle 207. The IR spectrum indicated the presence of hydroxyl and ester functions. The UV spectrum was identical with that of 49, a synthetic compound. A study of the NMR spectrum confirmed the 3,4,5-trisubstitution, the methyl ester,
8.
447
and a secondary methyl group. The magnitude of the coupling constants as determined by double resonance studies revealed the cis nature of the methyl and hydroxyl functions and confirmed that the methylene group is on the carbon adjacent to the ester function. The alkaloid therefore has structure 50, with absolute stereochemistry as shown (76). The possibility of its artifactual nature was noted.
c o 2 c * c H 3
N
49
c o 2 c * 3 :
N
50
c o 2 c 3 * :
0
51
OGlu
The same alkaloid was also isolated by Potier and co-workers (77) from Cantleya corniculata (Icacinaceae) and given the name cantleyine. Three principal fragmentation ions were observed in the mass spectrum of cantleyine (50), and these are thought to arise as shown in Scheme 4 (77). The location of the C-methyl group was deduced from an absence
+.
r
rnle 179
I
mle 207
na/e 207
l+.
t.
mle 175 SCHEME 4
mje 147
of nuclear Overhauser effect (NOE) when the methyl protons of the ester group were irradiated. Cantleyine (50),identical with the natural material, was obtained by treatment of loganin (51) with ammonia for 2 hours (77). The compound was not isolated from C. cornicuEata in the absence of ammonia.
448
GEOFFREY A. CORDELL
Two further isolations of cantleyine have been reported from Dipsacus azureus (78)and Strychnos nux vomica (79).I n both instances, ammonia was used in the work-up.
K. VENOTERPINE (GENTIALUTINE) (52) AND ISOGENTIALUTINE (55)

Another alkaloid of this same general type but lacking the carbomethoxyl side chain present in cantleyine (50)is venoterpine (gentialutine) (RW-47) (52). Venoterpine was first isolated from RauwolJia verticillata (Apocynaceae) by Arthur and Loo in 1966 (80) under the designation RW-47. Although some physical data were obtained, no structure work was carried out. Collaborative work on RW-47 with Johns and Lamberton (81)deduced two plausible structures for RW-47, of which one was favored on biogenetic grounds. The molecular ion a t m/e 149 in the mass spectrum and elemental analysis gave a molecular formula for RW-47 of C,H,,NO. Hydroxyl but no carbonyl absorption was observed in the IR spectrum. The UV spectrum indicated the presence of a pyridine and the 3,4 disubstitution was confirmed by the NMR spectrum. A secondary methyl group (doublet a t S 1.32 ppm) as well as a hydroxyl were observed (singlet 6 4.96 ppm, removed with D,O). This hydroxyl group was shown to be secondary, with the methine proton as a multiplet a t S 4.50 ppm. Double irradiation of this methine proton simplified the remaining benzylic region to an AB system and a quartet, the latter coupling with the methyl group. On this basis, the relative stereochemistry of the methyl and hydroxyl groups, which must be on adjacent carbons, was deduced t o be cis. Biogenetic reasoning suggested structure 52 for RW-47 (81). One feature remained to be explained, namely, the base peak in the mass spectrum a t m/e 120, a loss of 29 mu from the molecular ion. Deuteration shifted the base peak to mle 121, indicating that the hydroxyl proton was transferred in this process and -CHO lost. In 1968 Ray and Chatterjee (82) isolated venoterpine (52) from Alstonia venenata (Apocynaceae). Once again, the NMR spectrum gave important information for the purposes of structure elucidation, but the upfield shift of the hydroxyl group deceived the Indian workers into believing that they had a different stereoisomer than the Australian group. The coupling constants for the methylene and methine protons mitigated against this, however. Finally, RW-47 and venoterpine were compared directly (83) and found to be identical. I n addition, the ORD-CD spectrum of veno-
8.
449
terpine demonstrated that it was of the opposite absolute configuration to (A')-( - ) actinidine (38) (24, 50). Structure 52 therefore also represents the correct absolute configuration of venoterpine (83). Gentialutine was first isolated from Gentiana Zutea (84) and has subsequently been isolated from G. tibetica, G. asclepiadea (as),and Henyanthes trifoliata (86). The molecular weight was determined to be 149 (84, 87), which by elemental analysis could be ascribed to C,H,,NO. The compound lacked carbonyl absorption, but showed substantial hydroxyl absorption (84, 87). The UV spectrum was that of a vinyl pyridine, and on this basis, structure 53 was proposed (84). This structure was not supported by the NMR spectrum, which showed two a-pyridine protons a t 6 8.22 and 5.25 ppm and the /3-pyridine proton a t 6 7.15 ppm. The vinyl protons were not found. Instead, a methyl doublet was observed a t 6 1.35 pprn and the alcohol methine proton a t 6 4.60 ppm. Although these data negate structure 53 for gentialutine, no new structure was proposed a t this time. These data are, however, in agreement with the gross structure 52 for gentialutine, rather than that previously assigned (84). No stereochemical work has been carried out, but the close melting point of gentialutine with that of venoterpine indicated the probable identity of the two compounds. Recently, the structure of gentialutine was revised (88) and determined to be the same as venoterpine (52), although no direct comparison was made.
oH
52
53
54
55
Also obtained a t this time from Gentiana tibetica was a new alkaloid, isomeric with gentialutine, which was named isogentialutine (88).The IR spectrum indicated the presence of a hydroxyl function but absence of other functional groups. The UV spectrum demonstrated the presence of a pyridine derivative and from the NMR spectrum the substitution pattern was determined to be 3,4. I n addition, a threeproton doublet a t 6 1.33 pprn (secondary methyl) coupled to a proton at 6 3.18 ppm (benzylic methine) indicated a close similarity to gentialutine (52). Indeed, CrO,/pyridine oxidation of isogentialutine and gentialutine afforded an identical product, the five-membered ketone
450
GEOFFREY A. CORDELL
54, albeit a t differing rates. Gentialutine and isogentialutine, therefore, differ in the configuration of the hydroxyl group. Further evidence for this was obtained from the NMR spectrum, where the pyridylic methine proton appeared as doublet of doublets ( J = 7 Hz and 5Hz). The hydroxymethine proton gave coupling constants of 5 Hz and 3 Hz, indicating two trans- and one cis-oriented protons on adjacent carbon atoms. Isogentialutine therefore has structure 55 (88).
L.
LEPTORHABINE (57)
From the epigeal part of Leptorhabdos parvijlora (Scrophulariaceae), the Tashkent group recently isolated another new monoterpene pyridine alkaloid, to which the name leptorhabine was given (89).Permanganate oxidation under alkaline conditions pyridine 3,4-dicarboxylic acid (56),
56
57
thereby defining the substitution on the pyridine ring. The NMR spectrum confirmed this substitution pattern and also indicated a secondary methyl group and a benzylic hydroxyl group showing a methine proton at 5.06 ppm. Two methylene protons were observed as a multiplet at 1.98 ppm. On the basis of this and substantiating spectral evidence leptorhabine was assigned the structure 57, without stereochemistry.
M. BAKANKOSIDE (60)
Bakankoside was one of the first monoterpene alkaloids isolated, being obtained from seeds of the Madagascan Strychnos vacacoua (90). The name arises from the local name for seeds, bakanko. The highly stable crystalline compound was hydrolyzed by dilute acid to afford d-glucose (90).Hydrolysis with emulsin was not complete after 7 weeks (90). The high negative rotation ([.ID - 195") clearly aroused the attention of these workers. A further sample was obtained from the fruits of S. vacacoua (91), and subsequent work indicated a molecular
8.
45 1
weight of 359. Analytic data suggested (correctly) a molecular formula C,,H,,NOB + H,O for the parent compound and C,,H,,N03 for bakankoside itself (91). It was forty-four years before the work on bakankoside was resumed, this time by Prelogs group (92).It was demonstrated that bakankoside had no alkoxy, AT-methyl, or C-methyl groups; that it was neither acidic nor basic; and that it did not give derivatives for a carbonyl group or a color reaction with ferric chloride. Catalytic hydrogenation gave a dihydroderivative, and both bakankoside and the dihydroderivative formed tetraacetates. Osmium tetroxide oxidation of bakankoside and acetylation afforded hexaacetate, indicating the presence of a vinyl group. Dihydrobakankoside was hydrolyzed by emuslin to dihydrobakankogenin. I n 0.1 N sodium hydroxide, the UV maximum was shifted from 238 nm to 276 nm. No shift was observed for bakankosin. The shift is characteristic of the addition of a double bond in conjugation. Prelog and co-workers interpreted this as conversion of 58 to 59 (92).The IR spectrum confirmed the presence of an a$-unsaturated amide, showing two carbonyl bonds a t 1670 and 1625 cm-l. Zinc dust distillation of bakankoside gave crotonaldehyde, pyridine, and ,3-picoline. Several structures were proposed a t this time for bakankoside, but neither the carbon skeleton nor the relationship of the glucose to the rest of the structure could be deduced. Biichi (93, 94) subsequently suggested structure 60 for bakankoside, which accounts for the physical and degradative work, and this structure has remained unchallenged. The probable stereochemistry of bakankoside will be discussed later when biosynthetic aspects of the monoterpene alkaloids are discussed.
CC-C=C-C-N\
/
0
58
II
+ C=CC=CC-N\ II
59
OGlu
H
60
45 2
GEOFFREY
A .
CORDELL
N. GENTIANINE (62) Gentianine is the best known of the monoterpene pyridine alkaloids and is possibly the most widely distributed. Much of the early structure work on gentianinine was done by Proskurnina (95). Hydrogenation gave a dihydro derivative having a molecular formula CloH,,N02. Oxidation with permanganate gave an acid C,H,NO,. Distillation of this acid with zinc gave pyridine (95),and decarboxylation gave 4-vinylpyridine (96). Proskurnina and co-workers (96) originally assigned structure 61 to gentianine, but later (92') amended this to 62, since gentianine was optically inactive. I n addition, the I R spectrum also supported the presence of a 6 rather than a y-lactone (absorption a t 1715 cm-l).
61
62
63
At this time, Govindachari and co-workers (98, 99) synthesized dihydrogentianine (63) from 5-ethyl-4-methylnicotinic acid (64) by treatment with formaldehyde, thereby establishing the structure of gentianine (62). Subsequently, Govindachari and co-workers (100) synthesized gentianine by the route shown in Scheme 5 . I n 1963, the first NMR study of gentianine was published (101).The vinylic protons were observed a t 6 5.77,5.95, and 7.08 ppm, the pyridine protons a t 6 4.67 and 3.24 ppm. Prior to a study of the biosynthesis of gentianine, Marekov and Popov investigated the products of its oxidation (102). Gentianine, as can be seen from Table I, has been isolated from a number of plants, but often the question is raised as to its natural occurrence. Much of the early isolation work on the crude alkaloid fraction was done with the aid of ammonia, and there is no doubt that
8.
453
+
\
CONH,
HO
1. POCI. 2. PdCL, KOAc
SCHEME 5
in many instances gentianine was isolated as an artifact. Evidence for this comes from a number of sources. Swertiamarin, a secoiridoid isolated from Swertia japonica (103-109) and other species (110-115), was treated with ammonia for 3 days a t room temperature to give gentianine (116,117).Subsequent work with Anthocleista procera and Enicostemma littorale (118) indicated that swertiamarin was probably responsible for the gentianine isolated in these cases, since no gentianine was isolated in the absence of ammonia. The relationship to gentianine helped to establish the structure of swertiamarin as 65 (112). Similarly, another secoiridoid glycoside, gentiopicroside, has been shown to be transformed into gentianine by treatment with ammonia (119-121). Gentiopicrosidehas been isolated from a number of genera in the Gentianaceae (122) and has structure 66 (109, 123, 124). As far as possible, the isolation of gentianine from plants that contain swertiamarin or gentiopicroside and that have involved ammonia in the isolation procedure are designated by an asterisk in Table 1. A further problem has also been uncovered in the isolation of gentianine (81).The chloroform residue, after thorough extraction with acid buffer and treatment with methanol, deposited crystals having the elemental composition C,,H,,NO,Cl,. The UV spectrum indicated a great similarity to dihydrogentianine (63), and the IR spectrum indicated the presence of an unsaturated lactone and the pyridine nucleus. Oxidation with permanganate in acetone gave an acid (67) identical with that obtained from gentianine. The NMR spectrum confirmed the substitution showing two singlets a t 6 9.06 and 8.84 ppm. One methylene group was observed at 6 4.54 ppm and three methylene groups centered
454
GEOFFREY A. CORDELL
OGlu
65
66
67
68
at 6 3.00 ppm. On this basis, structure 68 was proposed for this chloroform adduct of gentianine (86).Treatment of a chloroform solution of gentianine with benzoyl peroxide also gave 68 (86).
0. FONTAPHILLINE (69)
Another plant in the Oleaceae giving rise to monoterpenoid alkaloids is Pontanesia phillyreoides, and this species has been investigated by Budzikiewicz (125).In addition to gentianine, a new crystalline alkaloid, fontaphilfine, was isolated. Elemental analysis indicated a molecular formula C18H,,N0,, and this was confirmed by the mass spectrum which showed an M + a t mle 327. Acid hydrolysis of fontaphilline afforded two components, identified as 4-hydroxybenzoic acid and gentianine (62).Fontaphilline was therefore suggested to be 69, and this structure was substantiated by spectroscopic data (125). The IR spectrum indicated a para-substituted benzene (850 cm- l), an aromatic carboxylic ester (1723 cm-I), and a hydroxylic group. The NMR spectrum indicated two pyridine a-protons as singlets a t 6 8.75 and 9.0 ppm, two pairs of ortho-aromatic protons a t 6 6.80 and 7.85 ppm, and a carbomethoxyl group as a singlet a t 6 3.95 ppm. A two-proton multiplet a t 6 5.60 pprn and ;t highly deshielded multiplet a t 6 7.30 pprn confirmed the presence of a vinyl group. The remaining two groups of methylene protons were observed as multiplets a t 6 3.60 and 4.55 ppm.
8.
455
The mass spectrum showed a molecular ion a t m/e 327 and a base peak a t m/e 121 having sructure 70. The electronegative mass spectrum however was more informative. The base peak appeared at mle 137 corresponding to the p-hydroxybenzoyl anion. Three other fragment ions were observed a t m/e 206 (ion 71), m/e 189 (fragment 72), and m/e 174 (ion 73), in agreement with the assigned structure of fontaphilline (125).
P. GENTIANADINE (74)
Gentianadine was first isolated from the aerial parts of Gentiana turkestanorum by Yunusov and co-workers (126). The crystalline base showed a carbonyl absorption at 1730 cm-l characteristic of a &lactone. The UV spectrum was similar to that of dihydrogentianine (63),but the elemental composition of C,H,NO, indicated a loss of two-carbon units (126). The base was apparently very similar to 74, a compound presynthesized by Govindachari and co-workers (99). Slight differences in physical properties were noted, however, and thus gentianadine was degraded to confirm this structure assignment. Alkali potassium permanganate gave pyridine-3,4-dicarboxylicacid and decarboxylation gave an oily product identified as 4-vinylpyridine. Gentianadine therefore has structure 74 (126). This structure was further confirmed by the NMR spectrum (127), which showed two-proton triplets at 6 4.52and 3.04 ppm for the lactone methylene groups and three pyridine protons at 6 9.12, 8.64, and 7.19ppm with coupling as expected. Its mass spectrum (128)gave the
456
GEOFFREY A. CORDELL
molecular ion m/e 149 as the base peak and important fragment ions by ring expansion and loss of CO a t m/e 120 and further losses of CO to m/e 92 and H C N to m/e 65. Gentianadine also occurs in G. olgae (129, 130) and G . olivieri (131). A novel route to its synthesis was recently described by Dolby and co-workers (132,133). The quaternary 2-dehydroquinuclidine-3carboxylic acid ester 75, when heated, rearranges via two consecutive 1,3 sigmatropic shifts to a mixture of 76 and 77, the former predominating. Palladium-carbon dehydrogenation afforded gentianadine (74) in 9% overall yield (132, 133).
74
75
76
77
Q. GENTIANIDINE(79)
From Gentiana macrophylla, Chinese workers isolated another monoterpene alkaloid type (134). Gentianidine was obtained in crystalline form and was optically inactive. The IR spectrum indicated the presence of a &lactone and alkali permanganate oxidation gave berberonic acid (78). N M R spectral evidence indicated probable structure 79 for gentianidine, and support for this came from condensation of 4,6dimethylnicotinic acid (80) and formaldehyde a t 100C (134,135).The
78
79
80
mass spectrum of 79 has been described (136). Gentianidine (79) has also been isolated from Erythraea centaurium (137),Menyanthes trifoliata (138), G . asclepiadea (112), and Xwertia japonica, but not from X. japonica in the absence of ammonia (139).
8.
457
R. GENTIANAMINE (81)
A further novel type of Gentiana alkaloid has been obtained from G. oliuieri (86, 126, 131) and G. turkestanorum (126).Gentianamhe is a crystalline alkaloid having a molecular formula C,,H,,NO,. The IR spectrum indicated the presence of hydroxy and %lactone functions and a double bond. The UV spectrum was very similar to gentianine. Monoacetylation confirmed the presence of a hydroxyl group (126),and catalytic reduction afforded a dihydro derivative, which contained a C-methyl group, thereby confirming the presence of a vinyl group. Alkali oxidation afforded pyridine 3,4,5-tricarboxylic acid (43). On this basis, gentianamine was assigned structure 82, and this was supported by the mass spectrum. The molecular ion, m/e 205, successively lost CH,O and CO, to give m/e 131 (126).I n addition, dihydrogentianamine (12) was syntheszed from dihydrogentianine (63); treatment with formaldehyde a t 100C gave a 50% yield of dihydrogentianamine identical with that prepared from the natural material. The NMR spectrum of acetylgentianamine (83) (127) indicated the presence of a vinyl group (absorption a t 6 5.8 and 6.94 pprn), two apyridine protons (8 9.06 and 8.85 pprn), and the acetate ( 6 2.04 pprn). Further assignments were not made.
+ o
N
81 R = H
q&Lo
N
82
CH, B r fN i o
84
83 R = Ac
C CH3 H O f i o
H H
85
S. GENTIOFLAVINE (85)
Gentioflavine was first isolated as Alkaloid IV from a number of Gentiana species (140).A molecular ion of C,,H,,NO, was derived from elemental analysis and mass spectrometry (140, 141). The IR spectrum
458
GEOFFREY A. CORDELL
shows the presence of an NH group (3235cm-l), conjugated lactone (1700cm-l), and a conjugated carbonyl group (1640cm-l). The NMR spectrum showed two methylene groups (4.35and 3 ppm), a methyl doublet (1.3ppm) with the corresponding methine proton a t 5.2 ppm. A singlet 1 0 . 1 ppm was ascribed t o an aldehyde group. The other two singlets a t 8.45 and 8.8 ppm were assigned to a n N H and another highly deshielded proton (141).The aldehyde group was confirmed by the formation of semicarbazone and oxime derivatives. Oxidation of gentioflavine with nitric acid gave pyridine 3,4,5tricarboxylic acid (43), and treatment with bromine water gave a basic compound, bromogentioflavine (C,H,BrNO,). The I R spectrum of this derivative indicated a S-lactone (1740em-l) and a pyridine ring. The NMR spectrum showed an aromatic methyl ( 6 2.76 ppm), the two methylene groups (6 4.57 and 3.16 pprn), and a n a-pyridine proton (6 9.03 ppm). On this evidence, structure 84 was assigned to bromogentioflavine (141,142).Treatment of bromogentioflavine with Raney nickel afforded gentianidine (79), identical with the natural product. Gentioflavine was therefore assigned the novel structure 85 ( l a l ) , bromine water affecting an oxidative decarboxylation of the aldehyde group (143). The mass spectrum of gentioflavine (136) showed an initial loss of 15 mu t o m/e 178 with subsequent losses of formaldehyde, CO, CO, and finally HCN t o give the cyclopentadienyl ion, m/e 65.
T. GENTIOCRUCINE (87), ENICOFLAVINE (go),AND GENTIANAINE (92)

Gentiocrucine was originally isolated by Marekov and Popov from Gentiana cruciata (142,144), and on the basis of spectral evidence structure 86 was assigned. Ghosal and co-workers have recently reinvestigated the structure of gentiocrucine isolated from Enicostemma hyssopifolium (145) and have concluded that in fact 87 is the correct structure for this compound. (145),indicating Gentiocrucine gave two 2,4-dinitrophenyIhydrazones that the formulation as an amide was erroneous. In the mass spectrum, a substantial loss of 27 mu was observed, and this could not be accounted for on structure 86 but could be accounted for by the loss of HCN from 87 (145). The PMR spectrum indicated the presence of adjacent methylene groups a t 6 2.4 and 4.3 ppm, two exchangeable proton a t 6 9.2 and 10.0 ppm, and a complex multiplet a t S 8.1 ppm. The latter was simplified to two doublets (J = 9 and 17 HE)on addition of D,O, indicating
8 .
459
the presence of cis and trans isomers of the methine proton on the vinylogous amide. The CMR spectrum of gentiocrucine conclusively demonstrated the existance of two isomers, fourteen carbon resonances being observed (88 and 89) (145).
CONH,
no
86
cis and trans

87
H.
\
97.42
35.70-
63.59
168.69
88
63.48
168.49
89
It should be noted that hydrogen bonding of the nonlactonic carbonyl in the cis isomer shifts this resonance downfield by 3 ppm to 194 ppm. As we shall see, gentiocrucine, although not apparently a monoterpene alkaloid turns out to be intimately involved with this group of compounds. Recently, Ghosal and co-workers have examined some of the more reactive monoterpene alkaloids, the concept being that there must be a number of intermediates between the secoiridoids and the normally isolated monoterpene alkaloids. From Enicostemma hyssopifolium, a new alkaloid, enicoflavine, was isolated, and the structures 90 and 91 were proposed for the isomeric mixture (146). Elemental and mass analysis established the molecular formula as C,oH,lNO,. Selective tlc sprays indicated the presence of an aldehyde (2,4-DNP and Tollens test) and the absence of a conventional nitrogen function (negative Dragendorf). The UV spectrum indicated the presence of a vinylogous amide cross-conjugated to a lactone group, a system found in gentiocrucine (145).I n the I R spectrum, bands were observed for NH/OH, an aldehyde, an unsaturated lactone function, and a vinyl group. The NMR spectrum (146) supported these functionalities, showing an aldehyde a t 6 9.3 ppm and vinylic and allylic methine proton in the
460
GEOFFREY A. CORDELL
regions 6 5.8-5.95 ppm and 6 6.8-6.98 ppm. The methine proton of the vinylogous amide was observed as a complex multiplet a t 6 8.2 ppm. Two two-proton multiplets for the lactone methylene were found a t 4.4 and 1.6 ppm, but more interesting were the radical changes in the spectrum on the addition of D,O. Peaks a t 6 10.1, 8.9, and 2.45 ppm were removed (three exchangeable protons) and the absorption a t 8 8.2 pprn simplified t o two singlets. The latter observation was taken t o indicate the presence of both cis and trans isomers, a phenomenon also observed with gentiocrucine (145). Enicoflavine (90) was found to be moderately unstable, being transformed a t room temperature into a mixture from which three components-gentianaine (92), gentiocrucine (77), and crotonaldehyde-were
isolated (146).The formation of these products can now be rationalized on the basis of the new structure of gentiocrucine as being a simple retroaldol reaction (Scheme 6).
SCHEME 6
Gentianaine, isolated from a number of Gentiana species (147),is also closely related to enicoflavine and gentiocrucine, although no biogenetic schemes have been previously proposed. The compound formed an O-acetyl derivative only with difficulty, although the IR spectrum indicated the presence of both OH and NH functions. The latter was associated with an amide group, and a n additional carbonyl absorption was observed a t 1718 cm-l (129). Some difficulty was encountered in analyzing the NMR spectrum of gentianaine (127).I n D,O, two two-proton multiplets were observed for the methylene protons a t 6 4.70 and 2.88 ppm, the former being a
8.
46 1
methylene adjacent t o nitrogen. A further signal at 6 8.50 ppm was ascribed to the aldehyde proton, which was confirmed by reaction with Tollens reagent. The spectrum of gentianaine in deuteropyridine showed two additional one-proton signals at 6 4.88 ppm for the hydroxy proton and 8.26 ppm for the amide proton. The enolic nature of the 1,3-dicarbonyl function could not be deduced from the spectrum (127). The mass spectrum of gentianaine (129) showed losses of CHO and CO to give ions m/e 11 2 and m/e 1 1 3 from the molecular ion a t m/e 1 4 1 . The base peak was at m/e 69, and the structure 93 was suggested for
H
92
93
this ion. This seems highly unlikely, since two protons would need to be lost from adjacent methylenes. More probable appears to be a synchronous loss of ethylene and HNCO from the M+ - 1 peak as shown (Scheme 7) to give the ion 94. Gentianaine is therefore another simple
H
SCHEME 7
m/e 69
94
derivative of a monoteqene unit, probably arising by loss of crotonaldehyde by retroaldol reaction from a compound such as 95, i.e., a hydroxybakankoside derivative.
H o A C H O
462
GEOFFREY A. CORDELL
U. JASMININE (96)
In 1968, Lamberton and co-workers (148) isolated another alkaloid derived from the secoiridoid skeleton. Jasminine, as the alkaloid was named, was obtained from a number of Jasminum species and from Ligustrum novoguineense. Subsequently, the same compound was isolated from a third member of the Oleaceae, Olea paniculata (149). Unique among the monoterpenoid alkaloids, jasminine was found to contain two nitrogen atoms and has the molecular formula C,,H,,N,O, (M+, m/e 220). Two intense carbonyl bands were observed-at 1725 cm-l attributed to an ester and a t 1680 cm-l attributed to an amide (148). I n the NMR spectrum (148) two a-pyridine protons were found a t S 9.01 and 8.57 ppm together with a broad signal a t S 8.17 ppm, exchangeable with D,O and assigned to the amide NH. A three-proton doublet at S 1.58 ppm was assigned to a secondary methyl group, and a three-proton singlet a t 8 3.93 ppm was assigned to the methyl ester function. The methylene protons were deshielded, appearing as quartets at 8 5.12 and 4.87 ppm, and the methine proton was also deshielded appearing as a broad multiplet at 8 4.75 ppm. Double irradiation studies confirmed the proton assignments. On this basis two structures, 96 and 97, were proposed (148) for jasminine, the former being considered more likely on biosynthetic grounds.
96
97
98
The mass spectrum (148)of jasminine shows a base peak of m/e 205 (loss of methyl radical) and subsequent important fragments a t m/e 173, 145, 118, 117, and 90. For structure 96, these fragments can be rationalized as in Scheme 8. Confirmatory evidence for the structure came from an examination of the concentrated acid hydrolysis product of jasminine, which, on the basis of spectroscopic evidence, was assigned the structure 98 (148).Chemical considerations indicate that hydrolysis would not be expected to result in decarboxylation of the acetic acid residue. Jasminine was not considered to be an artifact of isolation (148,149).
8.
463
mle 205
m/e 173
m/e 145
m/e
90
w
mle 118
pc,
SCHEME 8
v. GENTIATIBETINE (100)AND OLTVERIDINE (103)

I n 1967, Rulko and co-workers (150) described the isolation and characterization of a further type of monoterpene alkaloid. From the roots of Gentiana tibetica, a crystalline alkaloid was isolated (150) showing a molecular ion a t mle 165, which by elemental analysis correspond to C,H,,N02. The I R spectrum indicated the presence of a pyridine derivative and a hydroxyl group. The NMR spectrum substantiated the presence of a pyridine ring, but in this case substitution was 2,3,4, since two doublets (J = 5 Hz) were observed a t 6 6.85 and 8.21 ppm. A methyl singlet was observed at 6 2.53 pprn and was assigned to a methyl group a t the 2-position on a pyridine ring subjected to additional deshielding. A sharp singlet was observed at 6 5.94 ppm, suggesting a methine proton attached to two oxygen atoms. That one of these oxygens was a hydroxyl function was demonstrated by deuterium exchange. The four remaining protons were observed as separate, complex multiplets indicative of two adjacent methylene groups with differing chemical shifts. One pair of protons (6 2.56 and 2.98 ppm) was apparently benzylic, whereas the other pair (6 4.29 and 3.88 ppm) was adjacent to oxygen. I n the absence of carbonyl and vinyl groups, the structures 99 and 100 were proposed (150),the latter being favored on the basis of an enhanced deshielding of the methyl group by the proximate hemiacetal. Oxidation with chromium trioxide afforded a lactone 101. An interesting observation was made in the mass spectrum of this
464
GEOFFREY A. CORDELL
compound. The parent ion mle 165 loses 31 mu initially and subsequently 28 mu, but in the monodeutero compound (sample crystallized from C,H,OD) both these ions were shifted by one mass unit. This somewhat surprising result was rationalized in terms of a loss of formaldehyde from an M + - 1 species giving a species 102, which may lose CO, retaining the label (150).
HO
D
102
103
This alkaloid (100) has been named gentiatibetine (150),and has been isolated from a number of other species in the Gentianaceae (see Table I).Also isolated from G . oliwieri (131)was an alkaloid oliveridine, which gave spectral data similar to those of 100, but which from the mass spectrum was 14 mu larger. Loss of methoxyl from the molecular ion gave the base peak mle 148, which subsequently lost C2H, and CO. Structure 103 was proposed on this evidence and Scheme 9 was suggested to account for the mass spectral breakdown (131).This scheme should be compared with that proposed for the de-0-methyl derivative
m/e 179
mle 148
m/e 120
mle 91
SCHEME 9
8.
465
W. UNNAMED ALKALOID FROM Gentiana tibeticu

Chinese workers have isolated an alkaloid having the structure 104 from Gentiana tibetica (151). Evidence for the structure came mainly from the spectral properties after elemental analysis indicated a molecular formula C,,H, 1N03.The I R spectrum indicated the presence of a pyridine nucleus and a conjugated carbonyl. The latter functionality
104
was traced to an aldehyde (6 9.7 ppm) from the NMR spectrum. Also observed were a deshielded N-methyl group (6 3.26 ppm) and a slightly deshielded C-methyl doublet at 6 1.20 ppm, with the methine proton appearing a t 6 4.66 ppm, indicating proximity t o both an oxygen function and an aromatic system. The remaining protons were observed as two methylene groups a t 6 3.02 and 4.33 ppm. These data are in agreement with structure 104.
X. OLIVERAMINE (105)
Isolated from the chloroform-soluble alkaloids of G. olivieri (152)was a crystalline base that analyzed for C,,H,,NO, but that by mass spectrometry had a molecular weight of 352. The molecular formula was therefore C2,H2,N204, so that the compound is dimeric. Oliveramine, as the compound was named, gave a typical pyridine UV spectrum and showed the presence of a 6-lactone in the IR spectrum, and from the E value, two of these functions were demonstrated. Four aromatic 2,6-pyridine protons were observed, but no olefinic protons. A three-proton doublet a t 6 1.44 ppm indicated a secondary methyl, and four-proton multiplets a t 6 2.97 and 1.98 ppm accounted for the methylene groups of the 6-lactone. Two two-proton multiplets were also observed, corresponding to two adjacent methylenes, and the remaining methine proton was masked by other absorptions a t about 6 3.00 ppm. These data suggested structure 105 for oliveramine (152), which is therefore a reduced dimer of gentianine (62).
466
GEOFFREY A. CORDELL
105
296 mle
106
Mass spectral analysis of oliveramine indicated that a cleavage predominates t o give mle 176 as the base peak. A predominant alternate mode of fragmentation gives rise to m/e 296 (106) by successive losses of two carbon monoxide molecules (151).
Y. PEDICULIDINE (108) AND PEDICULININE (109)

Two further alkaloids of novel structure were isolated from Pedicularis olqae (153, 154). As we shall see, although both are C,, alkaloids, their terpenoid derivation is questionable in view of their structural nature. Pediculidine (153), having the molecular formula C,,H,NO, showed three maxima in the UV for an extended pyridine chromophore, and this was supported by the IR spectrum which indicated an unsaturated carbonyl function. The NMR spectrum of pediculidine confirmed the presence of an olefinic band, and from the observed coupling constant ( J = 12.2 Hz), it was cis-disubstituted. Three aromatic protons were observed, and from their chemical shift the pyridine ring was 3,4-disubstituted. The four remaining protons were in the 6 2.45-3.15 ppm region, corresponding to two deshielded methylene functions. On this basis, structures 107 and 108 were proposed (153) for pediculidine, the latter being favored on biogenetic reasons. No degradations were performed. Pediculinine (154),also isolated from Verbascum nobile (155),on the other hand, showed a characteristic pyridine UV spectrum and no bands in the carbonyl region of the IR spectrum. The molecular formula (C,,H,,NO) indicated the presence of a single oxygen atom and this was traced to a hydroxyl group from the IR and NMR spectra. Acetylation
8.
467
gave a monoacetyl derivative in which the methine proton had shifted from 6 4.01 ppm to 6 5.08 ppm. Substitution of the pyridine ring was found to be 3,4 from the NMR spectrum, and alkali permanganate oxidation to pyridine 3,4-dicarboxylic acid (56). The remaining protons were observed as a four-proton multiplet in the region 6 3.05-2.40 ppm and as two two-proton triplets at 6 1.98 and 1.57 ppm.
107
10s
109
Structure 109 was assigned (154) to pediculinine on the basis of this evidence. Pediculidine was not interrelated with pediculinine. Although structure 108 was chosen on the basis of biogenetic reasoning, it is not immediately obvious what the biosynthesis of these compounds involves. They are included here because of their Cl0 skeleton, and their co-occurrence with monoterpene alkaloids.
Z. PEDICULARINE (110), PEDICULARIDINE (113), AND PEDICULINE

Pedicularine was first isolated from Pedicularis olgae in 1963 by the Tashkent group (69) after separation of plantagonine (18) and boschniakine (44). The base was optically inactive and contained a carboxylic acid group. Subsequent work (156) indicated that the original material was a mixture. Separation by repeated recrystallization afforded pure pedicularine (mp 207"-209"C). The molecular formula was established to be C,,H,,N02, supported by a molecular ion a t m/e 177. The UV spectrum indicated a simple pyridine derivative, and the I R spectrum the presence of a carbonyl function (1710 cm-l). Alkali oxidation afforded pyridine 3,4-dicarboxylic acid (56) thereby establishing the substitution. The NMR spectrum confirmed this substitution, showing three pyridine protons a t 6 8.92, 8.47, and 8.07 ppm, the latter being coupled doublets. At 6 1.07 ppm, a three-proton doublet was observed corresponding to a secondary methyl group. TWO One-proton multiplets at S 1.67 and 2.18 ppm were assigned to two nonequivalent methylene protons, and the methine group for the
468
GEOFFREY A. CORDELL
methyl was observed a t 6 3.08 ppm. Also at 6 3.08 ppm, a second methine signal was observed, and on the basis of the two proposed structures 110 and 111, this would have to be assigned to the methine adjacent to the carboxylic acid (156).
110
111
113
The mass spectrum (156,157)indicated losses of methyl radical, H radical, and carbon dioxide by one fragmentation pathway and carbon dioxide followed by methyl radical in a second pathway, as shown in Scheme 10. Biogenetic consideration suggested that structure 110 was the more likely. The methyl ester of pedicularine (112)showed losses of methyl and carbomethoxyl as expected (157)(Scheme 10). Pedicularis olgae also afforded (158) an alkaloid, pedicularidine, closely related to pedicularine (110).The base was optically active and had a molecular formula C,,H,,NO. The UV spectrum confirmed the presence of a pyridine ring, and the oxygen function was traced to a saturated aldehyde or ketone from the IR spectrum. The mass spectrum showed losses of 1 mu and 29 mu, indicating the presence of an aldehyde, and this was confirmed when silver oxide oxidation afforded an amino acid identical, except for optical rotation, with pedicularine (110).The gross structure 113 was suggested (158)for pedicularidine. No stereochemistry was derived for this compound. I n 1968 the Tashkent group isolated from Pedicularis olgae a compound that they named pediculine (159).Elemental analysis and mass spectrometry indicated a molecular formula C,,H,,NO. The UV spectrum demonstrated the presence of a pyridine nucleus, and the IR spectrum indicated the presence of a hydroxyl group and no carbonyl group, thereby assigning the oxygen function. Hydrogenation gave an uptake of one molecule of hydrogen. The mass spectrum showed the molecular ion as a base peak and important fragment ions a t m/e 146 and mle 117. These ions were thought to be due to losses of methyl and formyl radicals. No NMR data were reported for pediculine. On the basis of this evidence, the impossible structure 114 was proposed (159)for pediculine. A number of possible alternative structures could be proposed for pediculine, and of these 115 seems reasonable as a working structure.
8.
469
T
u
x"
470
GEOFFREY A. CORDELL
CH,OH
114
115
The isolation and physical data for the monoterpenoid alkaloids are summarized in Tables I (160-198) and 11, respectively. Table I11 (199, 200) summarizes the isolation of a number of alkaloids of unknown structure from plants shown to contain monoterpene alkaloids.
111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids

The biosynthesis of the monoterpene alkaloids has been the subject of only limited study, and yet a considerable number of reviews of varying degrees of completeness have appeared (5-8,10,11,13-18,57, 122, 201-204). This biosynthetic work is reviewed here and is followed by a brief discussion of related areas of iridoid biosynthesis and an outline of the biogenesis of the monoterpene alkaloids. The problem that possibly some or even all of the monoterpenoid alkaloids may be the result of addition of ammonia to a preformed iridoid or secoiridoid during work-up has been the subject of some discussion. Whereas yields of alkaloid isolated are sometimes unaffected by the use of sodium carbonate in place of ammonia (76,119),in other cases, no alkaloids are isolated in the absence of ammonia (77,118,119), and in some instances the yield of alkaloid is merely increased by the use of ammonia (197). The leading work in this area is that of Floss and co-workers (119), who found that 91% D f [15N]gentianine (62) from G. lutea was from added labeled ammonia. Only G. fetisowii afforded similar quantities of gentianine by procedures involving ammonia and sodium carbonate.
A. SKYTANTHINES
I n 1961, the skytanthines were suggested as belonging to the monoterpene group of alkaloids (21),and subsequent work has confirmed this concept. Feeding [2-14C] mevalonate (116) to Skytanthus acutus (205) afforded, as predicted (206), radioactively labeled skytanthine (a), whereas labeled phenylalanine and acetate gave an inactive product
TABLE I ISOLATION OF MONOTERPENE ALKALOIDS Alkaloid Plant name Reference"
I. Iridoid-derived
Actinidine (37)
(+)-Boschniakine (44) (indicaine)
(- )-Boschniakine ( )-Boschniakinic acid (18) (plantagonine)
Actinida arguta Franchiet Sav. A . polygama Miq. Tecoma fulva G . Don T . radicans Juss. Valeriana oficinalis L. Boschniakia rossica G . Beck Pedicularis ludwigi Regel P. olgae Regel Plantago albicans L. P . indica L. P. major L. P. notata Lag. P . psyllium Dene. P. ramosa Aschers. Tecoma rndicans Juss. T . stuns Juss. Incarvillea olgae Regel Boschniakia rossica Pedicularis dolichorrhiza Schrenk. P. ludwigi Regel P. olgae Regel Plantago albicans P . coronopus L. P. crassifolia Roth P. crypsoides Boiss. P. cylindrica Forsk. P. indica P. major
56 24, 54, 55 59 56 57, 58 24 160 69-71 60, 61 67, 71 60 61 161 68 41 56, 57 162 24 163 160 46,69-ri 60, 61 60 60 60 60 67 60
(continued)
a ,
TABLE I (continued) Alkaloid Plant Name Reference'

60, 61 60 161 68 164 162 77 78 76 79 36, 57 52 23, 52, 53 53 74 88 89 42 41 19-23, 29, 31, 33, 165, 166 36, 57 33-35 59 39-42, 57 42, 44, 57 44 46 82 86 84
I&
tQ
P. notata P. ovata Forsk. P. psyllium P. ramoea

(-)-Boschniakinic acid Cantleyine (50)
Verbascum songaricum Schrenk. Incarvillea olgae Cantleya corniculata Dipsacus azureus Schrenk. Jasminum species NGF 29929 Strychnos n u x vomica L. Tecoma s t a m Skytanthus acutue Meyen Skytanthus acutus Skytanthus acutus Pedicularis olgae Gentiana tibetica King Leptorhabdos parwifolia Tecoma stans Tecoma stans Skytanthus acutus Skytanthus acutus Skytanthus acutus Tecoma fulva G . Don Tecoma etans Tecoma stuns Tecoma stuns Pedicularw rhinantoides Hook. f Alstonia venenata R. Br. Gentiana asclepiadea L. G. lutea L.
A5-Dehydroskytanthine(28) A'-Dehydroskytanthine (27) Hydroxyskytanthine I (22) Hydroxyskytanthine I1 (21) Indioainine (46) Isogentialutine (55) Leptorhabine (57) 4-Noractinidine (48) N-Normethylskytanthine (47) Skytanthine (4) S-Skytanthine (8) 8-Skytanthine-N-oxide (9) Tecomine (13) Tecostanine (16) ( - )-Tecostidine(17) (+)-Tecostidine (19) Venoterpine (52) (gentialutine)
Unnamed Unnamed Unnamed Unnamed
I (24) I1 (25) I (38) I1 (39)
G.tibetica Menyanthes trifoliata L. Rauwolfia verticillata (Lovr.) Baill. Tecoma stans Tecoma s t a m Valeriana oflcinalis Valeriana oflcinalis
85 138 80, 81 41 41 57, 6 4 , 65 65
1 1 . Secoiridoid-derived
Bakankoside (40) Enicoflavine (90) Fontaphilline Gentianadine (74)
Gentianaine (92)
Gentianamine (81) Gentianidine (79)
Gentianine (62)
Strychnos vacacoua Baill. Enicostemma hyssopifolium (Willd.) Verdoorn Fontanesia phillyraeoides Labill. Gentiana olgae Regel G.olivieri Griseb. a. turkestanorum Gandoger Gentiana caucasa Bieb. G. kaufmanniana Regel e t Schmalh. G. olgae Q. olivieri G. turkestanorum Gentiana olivieri G.turkestanorum Erythraea centaurium Pers. Gentiana asclepiadea G.macrophylla Pall. Menyanthes trifoliata Swertia japonica Makino Anthocleista procera Lepr. A . rhizophoroides Baker Centaurium pulchella Hayek Dipsacus azureus Enicostemma littorale 331. Erythraea centaurium
90, 91 146 125 129, 139 126, 131 126 129 129 129 129 129 87, 126, 131 126 137 87 134, 167 138 139 101*, 111*, 113*, 168* 169 170 171-1 74 99*, 118*, l75* 137*, l76*, 177, 178
(continued)
Po
4 4 W
TABLE I (continued) Alkaloid

Plant Name
Fagrea fragrans Roxb. Fontanesia phillyreoides Labill. aentiana angu.stifoZia Michx. C . asclepiadea G . axillariJora Lev. et Van. B. axillaris Reichb. 0. barbata Froel. a. biebersteinii Bunge a. bulgarica Velon 0. clusii Perr. et Song. a. cruciata L. a. decumbens L. f. 8. dinaerica G. Beck G . fetisowii Regel et Winkler G . freyniana Bornm. 0. gracilipes Turrill Q. kauffmanniana U. Zutea a. macrophylla Pall. Q. olivieri B. pneumonanthe L. a. punctata L. Q. purdomrii Marquand a. purpurea L. a. scabra Bunge B. schistocalyx C. Koch 0. septem$dea Pall. a. sino-ornata Balf. a. straminea Maxim.
Reference"
179, 180 125 119% 86, 140*, 168*, 181*, 182 183 184 184 185 140* 119* 119*, 140*, 186* 184 119* 119 119* 119* 129 84, 119*, 140, 181* 147, 184, 187 87, 126, 131, 177 188 140* 119* 181* 183* 185 119*, 185 119* 119*
B. tianschanica Rupr. B. tibetica

Q. turlcestanorum
a. viriiowi
G. vvendenakyi Grossheim
B. wutaiensis Merquand
Ixanthus wiscosus Griseb. Lomatogonium rotatum Fries. Menyanthes trifoliata Ophelia diluta Ledeb. Swertia connata Schrenk S.graci$ora Gontsch. S.iberica Fisch. 8. japonica Makino S. marginata Schrenk Bentiana mclepiadea 0. lutea B. olivieri B. punctata B. p u r p r e a B. tibetica Menyanthes trgoliata Enicostemma hyssopifolium Qentiana cruciata Erythrea centaurium Bentiana mclepiadea B. bulgarica B. cruciata B. lutea Q. olgae a. olivieri B.punctata Q. tianshanica
Gentiatibetine (100)
Gentiocrucine (86) Gentioflavine ( 8 5 ) .
130, 189 85, 119 126, 190 95 130 119* 191 184 138, 181 184 130 171 185 139*, 183*, 192, 193* 172 86, 181 181 87, 131 140, 142, 158 181 151 138, 181 145 142, 144 137 140,194 140 140 140, 141 130 131, 151 140, 195 130
(continued)
00
4
Cn
TABLE I (continued) Alkaloid Plant Name Reference4
Jasminine (96)
Oheramine (105) Olivericline (103) Pedicularidine (113) Pedicularine (110) Pediculidine (108) Pediculinine (109) Unnamed I (104) 111. Unknown structures Alkaloid I Alkaloid I1
Swertia connata S. gracilifolia Gentsch. 8.marginata Jasminum domatiigerum Lingelsh. J. gracile Andr. J. lineare R. Br. J. schumannii Lingelsh. Lingustrum novoguineense Lingelsh. Olea paniculata R. Br. Gentiana olivieri Gentiana oliveri Pedicularis olgae Pedicularis olgae Pedicularis olgae Pedicularis olgae Verbascum nobile Vel. Gentiana tibetica
130 172 172 149 149 149 149 149 150 152 131 158 69, 156 153 154 155 151
M 0
*
c
Alkaloid IVb Alkaloid V
Gentiana asclepiadea G. punctata Gentiana asclepiadea 0. bulgarica G. cruciata . G. lutea G. punctata Gentiana cruciata Gentiana asclepiadea
140 140 140 140 140 140 140 196 197
cf. bulgarica
B. cmciata B. lutea B. punctata

Alkaloid VI
Bentiana aaclepiadea
B. bulqarica
Q. cruciata
Alkaloid B Alkaloid B Alkaloid C Alkaloid E Gentianamine (81)
Qentiana macrophylla Skytanthus acutus Bentiana macrophylla Skytanthus acutus Bentiana caucasia B. kauffmnniana B . olqae Q. olivieri a. tianthanica a. turkestanorum 0. vvedenskyi Swertia conmta S . qraciJEora S . marginata Pedicularh dolichorrhiza Plantaqo albicans P . indica P . notata P . ovata P . psyllium Bentiana olivieri Pedicularis olqae Centaurium spicaturn Fritsch.
Indicanine
Oliverine (105) Pediculine (115) Spicatine

a
197 197 197 197 140 140 140 147 23 147 23 129 129 129, 130 126 130 126 130 I30 172 172 163 60, 61 67 61 60 161 87, 131 I59 198
Po
Asterisk indicates that ammonia was involved in the isolation procedure.
TABLE I1
PHYSICAL PROPERTIES OF THE MONOTERFENE ALKALOIDS
uv
Alkaloid Molecular Formula mp/hp (mm)
IR spectrum
spectrum A,,, (log c)
NMR spectrum ( 6 ppm)

1.27 (d, 3) 2.18 (s, 3) 8.01 (s, 1) 8.11 (9, 1) (20)
Mass spectrum
(We)
147, 120 ( 6 4 )
[ a ] ~
Salts and derivatives Picrate mp 143'C ( 2 4 , 55, 61, 62, 65) mp 146.5-147.5-C (59) Hydrochloride (61, 6 4 )
Synthesis
( + ) form (50, 51)
I. Iridoid-Derived Actinidine (37)
100-103C 191 ( 6 4 ) (24, 54, 55, 61, 6 2 )
-7.9" ( 2 4 , 62, 6 4 )
- 13"(59)
( - ) form (21, 60, (f 62, ) form 6 4 , 65) (PO, 40,
Boschniakine (44) (indicaine)
SO-90C [3] (24) 214-216C

($9)
(zjr,41)
239, 268, 282

(24)
1.38 (d, 3) 8.77 (9, 1) 8.99 (9, 1) 10.45 (s, 1)

(41)
Boschniakinic acid (18) (plantagonine)
+ ) 218-220C
( 2 4 , 62,67,
(24, 69,162)
(70,71,162)
69,160)
( - ) 218-22ooc
(162)
( +) 226-227C
(162)
1.15 (d, 3) (70) 1.32 (d, 3) 9.15 (s, 1) 8.64 ( 8 , l ) (71) Methyl ester (47)
Cantleyine (50)
132-133OC
(76)
(76, 77)
271 (3.39) (76, 77)
130C (77)
1.31 (d, 3) 3.78 (s, 3) 8.29 (s, 1 ) 8.77 (s, 1) (76,77)
45, 62, 63) Picrolooate (61) N 0xi de mp 124OC ( 6 1 ) Picrate 161, 146, 132, + 2 l 0 ( 2 4 ) 118, 117, 91, mu 120-128C (ZJ, ( ) form ( 2 4 ) 77 (70,73, 73) + 57.6' ( 6 9 ) mp 151-153C ( 6 7 , ( ?1) form ( 2 4 ) 196) 68. 162) mp 153-154% ( 1 6 0 ) From boschnia177, 162, 146, 38.6' (69) Picrate kine ( 2 4 , 68, 70 mu 159-160C 133. 118. 91. 70, 71,162) 30.8' (67) 77 (70,Y1, (67) mp 165-167C(160) 196) From twostidine -30.1' Hydrochloride 162 (46, 48) mp 228-230C (67) Nitrate mp 147-148C ( 6 8 ) Chloroaurate mp 151-153OC (67) Methyl ester mp 40-41C ( 6 9 ) Ethyl ester mp 43.5"C ( 6 8 , 6 9 , 71) From loganin (77) 34' (76) 207, 179, 176, 147, 132, 117, 40' (77) 91, 77 (76, 77)
+ +
As-Dehydroskytanthine CllHlsN (36)

(28)
_-
(36)
1.0 (d, 3) 1.3 (d, 3) 2.9 (9, 3) 5.5 (m, 1) (36)
165, 150,122, 107, 79, 58, 44 (36)
-89" (36)
Picrate mp 167C (36)
A7-Dehvdrosk~tanthine C,,H,.N (29. . . . . . , (29) 52, 53) Hydroxyskytnnthlne I CllHPINO ( 5 2 ) 93C (23, 52) (22) (alkaloid D) 94-95OC (53) Hydroxyskytanthine I1 (21) Indicainine (46) Cl1HlaNO (53) 119-120C (53)
__
(52)
1.50 (s, 3)
(52)
(53)
0.82 (d, 3) 1.24 (s, 3) 2.3 (s, 3)
Yethiodide m p 235-237"C(36) Picrate From hydroxymp 127C ( 2 9 , 5 2 ) skytanthine (53) +35.8' (23, Methiodide m p > 300'C (dec.) (23) (23, 52) 38.5" (53)
(52)
CiaHieN + 0
(74)
(74)
261 (3.52) 268 (3.48)

(74)
1.00 (d, 3) 1.12 (5, 3) 2.18 (s, 3) (53) 3.49 8.55 (s, 1) 8.75 (9, 1) 10.13 (s, 1)
(74)
110, 84, 58, 44 -38.5'(53) (53) 190,162,161, + 14.2O 146, 133,132, ( 7 4 ) 118, 117, 91, 77 ( 7 4 ) 149, 120, 105, 98, 79 ( 8 8 )
Picrate m p 125-127C ( 7 4 )
Isogentialutine (55)
CsIIllNO ( 8 s ) 131C (88)
(88)
5 CD
254,260,267 (88)
Leptorhabine (57)
CsIIiiNO (89)
(89)
263,269 (89)
1.33 (d, 3) 3.05-2.98 (m, 2) 3.18 (m, 1 ) 3.69 (b, 1) 4.53 (td, 1) 7.15 (d, 1 ) 8.28 ( 8 , 1) 8.28 (d, 1) (88) 1.20 (d, 3) 1.97 (m, 1) 3.30 (m, 2) 5.06 (m, 1) 6.94 (bs, 1) 7.15 (d, 1) 8.07 (d, 1) 8.11 (4, 1)
(89)
149, 132,131, 118,117,106, 79 (89)
4-Noractinidine (48)
CBHIIN( 4 1 )
(41)
8.03 (d, 1) 8.8 ( 5 , 2) 8.85 (d, 1 ) 1.6 (d, 3)

(41)
+3" ( 4 1 )
PIcrate m p 135-137C ( 4 1 )
(continued)
TABLE II(continued)
uv
Alkaloid N-Normethylskytanthine (47) Skytanthine (4) Molecular Formula mp/bp (mm) 125130' (3)
(41)
IR spectrum
(41) (19, 165)
A,,,
spectrum (logs)
NMR spectrum (8 ppm)

0.9 (d, 3) 1.02 (d, 3) (41) 1.27 (d, 3) 2.18 (s, 3) (19, 20, 165)
Mass spectrum
(mid
[a]=
Salts and derivatives Picrate mp179-18O0C(41) Picrate mp 127-128OC (19,

21, 165)
Synthesis
CloHlsN (41)
ClIHZ1N
(19,-21, 165)
153 (41)
+35" (41)
54" (1.5) (21, 22) 62" (1) (23) 62" (1.5) (19,
21, 165)
+ 42' (20,
+ 26.8 (32)
+ 32 (23)
22)
mp 132-133C (23,
32)
mp 133-13SOC (20,
22, 29.32)
mp 1 4 1 T )28) Picrolonate mp 210-218OC (19,

21, 165)
Perchlorate mp 177C (23) mp 180C (32) Hydrochloride (21, 22, 16.5) Hydrobromide (21.22, 165) Methiodide mp 296-298C (20, 22. 23) mp 305-308T (19,
21, 165)
a-Skytanthine (5)
+ 79" (25) + 16' (25) + 59" (25)
@-Skytanthine (6)
(30)
4.4'-Dichloro~hen~lsulflmide (32) Picrate (25. 27, 28) mD 120C (25.2729, 166) Methiodide mp 237-239C (30) Picrate (25) mp 135C (25,29,
166)
y-Skytanthine (7)
(30)
Methiodide mp 295-298'C (30) Picrate mp 162OC (35,37) Methiodide mp 3O8-31O0C (30)
(25, 27, 30)
&Skytanthine (8)
167,186,152, 110, 84, 58, 44 (30, 36)
+ 10"
(25, 3 6 )
Picrate m p 139C (25, 27,

29, 1 6 6 )
( 2 5 , 27. 28, 30)
Prom As-dehydroskytanthine
(36)
&Skytanthine "oxide (9) Tecomine (13) (tecomanine)
CllH2,NO218-222% 2H20 ( 3 3 , 3 5 ) (33, 35) 125C (0.1) CI1Hl7NO

(39-41) (40,41)
(35) (39-41)
226 (4.1)
(39-41)
1.07 (d, 3) 1.12 (d, 3) 2.75 (5, 3) 5.95 ( 8 , 1)

(40, 41)
0' ( 3 5 )
-175" (40,
- 160'
41)
m p 144-146OC ( 3 6 ) Methiodide m p 300-302C (36) m p 303-305C ( 3 0 ) Picrate m p 187-190'C (35) Picrate m p 179-18OOC (40,
41,59
From B-Skytanthine (33,35)
(59)
Methiodide m p 240-242OC (40,

41)
Tecostanine (16)
CllHllNO
(4~~44)
82OC (42, 44)
(42, 44)
0.98 (d, 3) 2.25 (9, 3) 3.56 (d, 2)

(44)
100. 58. 44 ( 4 4 ) 0' ( 4 2 . 44)
2,4-DNP m p 260C (39) Hydrochloride m p 262C (42) Methiodide m p 245C ( 4 0 ) Acetate ( 4 2 ) Picrate m p 151-152OC ( 4 6 ) m p 152-153C (45) Acetate ( 4 5 )
Tecostidine (17) and (19) CIOIIllNO

ifr
(45, 46)
(45, 46)
c o
Venoterpene (52)
C&llNO
(80,81,84)
13&132OC
(80.81)
(81-85, 88)
259 (3.50) (81-85, 8 8 )
128-130C
(82, 84,8688, 1 3 8 )
Unnamed I from Tecoma slam (24)
CloHziNO
(41)
91-92OC
(41)
(41)
(41)
163 (45, 46) 1.27 (d, 3) 4.65 ( 8 , 2) 8.22 ( s , 1) 8.27 ( s , 1) (45) 1.32 (d, 3) 149, 134,132, 2.9-3.3 120,106.77 (80-82) (m, 3) 4.50 (m, 1) 5.60 ( 6 , l ) 7.09 (d. 1) 8.18 id, 1) 8.21 ( 8 , 1) (81-83. 85.88) (Benzoate) (41) 0.9 (d, 3) 1.0 (d, 3) 2.3 ( 8 , 3)
(41)
-4" ( 4 5 ) +5.ga ( 4 6 )
( + ) form (48, 49)
+ 27" (80, 81)
Unnamed I1 from T e c m slam (25)
CloIIzlNO
(41)
82-94'
(41)
(41)
(41)
0.95 (d, 3) 1.24 (d, 3) 2.27 (9, 3)
183, 166, 150, 74,55 ( 4 1 )
Picrate m p 170C ( 4 1 ) Methiodide m p 293-295C (41) Benzoate m p 60-65OC ( 4 1 ) Methiodide m p 310-312C ( 4 1 )
(continued)
TABLE I1 (confinued)
uv
Alkaloid Unnamed I from Vnleriana ofleinalii, (88) Molecular Formula ClsHazNOCl mp/bp (mm) 201-203C
IR spectrum
(64)
Amax
spectrum (log e)

1.23 (d, 3) 2.34 (s. 3) 4.73 6.73 (d, 1) 7.04 (d, 1) 8.83 ( 8 . 1) 8.90 (s, 1)
(64,65) (65)
Mass spectrum
(mle)
288, 147, 132, 120 (.6 4. . 6 5.)
[alD
Salts and derivatives
Synthesis
( - ) form ( 6 5 )
222, 267 ( 6 4 )
4.50.5' (64) Picrate
im, 4)
ma 151-152'C (.6 4 . .
65) Tritluoroacetate mp 201-203C ( 6 4 ) Methyl ether mp Ill-113C ( 6 4 ) Acetate ( 6 5 ) + 19.3" (65) Picrate mp 65-70C ( 6 5 )
(
+ ) form (57)
Unnamed I1 from Valeriana offkinalin
(65)
(39)
11. Secoiridoid-derived
Bakankoside (60) 157" and 200C
(90)
240, 270 ( 1 4 6 ) 1.6 (m, 2) (146) 2.45 (b, 1 ) 4.4 (m, 2) 5.8-5.96 (dd, 2) 6.9-6.98 (m, 2) 8.2 (m, 1) 8.9 (b, 1) 9.3(s, 1) 10.1 (b,1) (116) 212 (4.49) 3.60 (t, 2) 257 (4.25) 3.95 (s, 3) (125) 4.55 ( t , 2) (125) 5.60 (m, 2) 6.80 (d, 1) 7.30 (m, 1) 7.85 (d, 1) 8.75 (9, 1) 9.00 (5, 1)
(125)
(99)
162" and 211OC
, +
00 N
(93)
Enicoflavine(90)
Fontaphilline (69)
80" and 121C ( 1 2 5 ) (125)
Gentianadine (74)
C8H7NOz (126) 77-78C ( 1 2 6 , (126) 129) 76-77C ( 1 3 2 ,

133)
8748C (99)
3.04 ( t , 2) 4.52 (t,2) 7.19 (9.1) 8.64 (d, 1) 9.12 (d, 1)

( 127)
149, 120, 92, 65

(128)
Picrate (99, 1 3 2 , 1 3 3 ) mp 153C ( 9 9 ) mp 156C ( 1 2 6 ) From gentioHydrochloride flavine ( 1 4 1 ) mp 195-196C ( 1 2 6 )
Gentianaine (92)
CeH,NO, (127, 149-150C 129) (127, 129)
(129)
231 (4.16) 268 ( 4 . 1 ) ' (129)

(126)
Gentianamine (81)
CIIH~INOB 149-150C (126) (126)
(126)
2.88(4.16) 4.70 im, 2 ) 8.50 (m, 2 ) (137) 5.80(q, 2 ) 6.94 (rl, 1) 8 . 8 5 (a, 1 ) ) 9 . 0 6 (a, 1 (127)
141. 113.112.69 (iz.9)
Acetate m p 164-165C (129) 2,4-DNP (127) Picrate mu 1 4 6 1 4 7 ' C (126) Nitrate mp 127-128C( 1 2 6 ) Oxalate mp 158-159T (126) Methiodide mD 157-158C( 1 2 6 ) Acetate mp 96-97OC ( 1 2 6 ) Dihvdro mp 170-171C ( l ? 6 ) (134,135) From enicoflavine (146) Picrate mp 122-124C(147, 176. 186.191 From fontaphilOxalate mp 1 5 2 1 5 3 ' C line (125) ( 9 5 , 147, 176, 183,186) Methiodide From gentiopicromp 188-199T( 8 2 , aide (120,121 95, 99, 147, 186, 187) Hydrochloride From swertmp 1 6 9 1 7 0 ' C (84, iamarin ( 1 1 3 , 99, 168, 176, SB, 116, 118) 183, 1 8 6 , 1 9 1 ) Hydrobromide mp 176-178C( 8 4 , 95. , 99.147.183) , . . Nitrate mp 238-239C ( 8 4 , 95)
205,175, 131, 117,91 (1,OG)
Gentianidine (79) Gentianine (62)
CgHsN02 ( 1 3 4 , 139) CIOH.O, (95, 125, 176)
(134) 129-13OoC (134,137) (137-139) (84. 85, 99, 8042C ( 8 4 , ( 8 4 , 85, 97, 85, 85, 99, 9 9 , 101, 175, 101, 147, 191) 169) 101, 113, 138, 147, 168, 171, 176, 181, 183,1X6) 83C ( 1 3 8 , 1 9 3 )
(134) (101,113)
(136)
175,147,117, 91 ( 1 2 5 )
Gentlatibetine (100)
CsHllNOa (150)
159-160C (150) (131) 161.5"C ( 8 6 , 138, 150)
(150)
2 . 5 3(a, 3 ) 2 . 5 6(m, 1) 2.98(m, 1) 3.88 (m, 1 ) 4 . 2 9 (m, 1 ) 5.94(a, 1 ) 6.85(d, 1) 8.21(d, 1 ) (150)
165 134 106 (150)
(continued)
TABLE I1 (continued)
uv
Alkaloid Gentiocrucine (86) Molecular Formula CeR7N03( 1 4 4 ) mp/bp (mm)
IR spectrum
(144)
spectrum Amax (log 6)
Mass spect,rum
(mid
DI.[
-
Salts and derivatives 2,4-DNP I mp 214-216C (145) 2,4-DNP I1 mp 194-195OC (145) Semicarbasone mp 221-223C Oxime mp 203-205C
(141, 142)
Synthesis
232, 283 ( 1 4 4 ) 2.58 (m, 2) 4.40 (m. 2) 8.10 (bd, 1)

(144)
141,113 111,97 (144)
Gentioflavine(85)
CioHllNOB
(140, 141)
207-208C
(171)
(140,141)
235,298, 410
(140,141)
218-220C (140-I 42)
1.3 (d, 3) 3.0 ( t , 2) 4.35 (t, 2) 5.2 (9, 1) 8.45 (9, 1) 8.80 (a, 1 ) 10.10 (8, 1)
(141)
Jasrninine (96)
CiiHmNzOQ
(148)
175-176OC
(248,149)
(148)
1.58 (d, 3) 4.75 (rn, 1) 4.87 ( % I )

5.12 (%I)
220,205, 173, -33" ( 1 4 9 ) 145, 118,117, 91 ( 2 4 8 ) -37.5"(148)
8.57 (8, 1) 9.01 (8, 1)

(148)
1.44 (d, 3) 1.98 (m, 2) 2.67 (m, 2) 2.96 (m, 5 ) 4.46 (m, 4) 8.43 (8, 1) 8.76 (8, 1) 8.94 (8, 1) 9.00 (s, 1)
352, 296,176 (152)
Ollveridine (103) Pedicularidiue (113) Pedicularine (110)
C~OH~ONO 260C ~ (132)

(131)
(152) (131) (258) (131)
CloH1,NO
(158)
211-212OC
(158)
236 (3.36) 270 (3.32)

(158)
8.07 8.47 8.92

(156)
179, 151, 148, 120, 91 (131)

(158) (156-158)
f67.7" (158)
Nitrate ( 6 9 ) Methyl ester (157, 1 5 8 )
From grentiotibetine (131)
C I O H ~ ~ N O Z203-204C
(156,157) (158)
(156, 158)
272 (156,
158)
' 0 (69) - 15.3"

(256)
f
207-209C (dec.) ( 6 9 ,
156)
From pedicularidine (158)
52.9"
(158)
Pediculidine (108)
CioHgNO (153) 74-75C (253) ( 2 5 3 )
268 (3.97) 273 (3.96) 293 (3.36)

(153)
2.45-3.15 (m) 6.34 (d) 7.12 i d j 7.15 (d)
159, 158, 131, Picrate 130. 118. 117. 104,' 103,' 102,' 77 (153)
Picrate mu 211-212C ( 1 5 3 )
8.41 (d) 8.51 (9)
Pediculinine (109)
CIOHI~NO
(154)
133-134C
(154,155)
(154)
262 (3.33) 269 (3.23)

(154)
1.57 ( t , 2) 1.98 (t, 2) 3.05-2.10 (m, 4) 4.01 (m, 2) 6.93 (d, 1) 8.19 (rn, 2)
(154)
(153)
161, 146, 145, 131, 130, 118, 117, 91, 77

(154)
Acetate (15d)
Unnamed from G'entiana CloH,,NO3 tibetica ( 1 0 4 ) (151)
208-210C
(151)
(151)
234 (4.21) 296 (4.32) 402 (3.95)

(151)
1.20 (d, 3) 3.02 (m, 2) 3.26 (s, 3) 4.33 (m, 2) 4.66 (u. 1) 7.74(s, 1 ) 9.70 (s, 1)
(151)
0.80 ( 1 5 1 )
111. Unknown Structures

Alkaloid I Alkaloid I1
C13HteNaO3
(140)
183-187C (140)
269,316 ( 1 4 0 )
I
138-140C
(197) 240C ( 1 9 7 )
248-252OC (140) 128-130C

(147)
234, 266 ( 1 4 7 )
190C (15) (23) 206-208C

(147)
120-140C (28) 375-380C

(126, 129)
161, 146, 117, 91 ( 1 5 8 )

1
206-207C (131) 188-189T

(189)
+ 61.5" ( 1 5 9 )
-
Picrate mp 127-129C ( 6 7 , 163)
182-183C
(198)
486
GEOFFREY A. CORDELL
POSSIBLE ISOLATIONS O F
TABLE I 1 1 MONOTERPENE ALKALOIDS (UNIDENTIFIED) mp/bp ("C) Reference 197 197 197
Compound Alkaloid I 1 1 Alkaloid I 1 1 Alkaloid I 1 1 (aerial parts) Alkaloid I 1 1 (roots) Alkaloid 111-1 Alkaloid 111-2 Alkaloid IVa Alkaloid VII Alkaloid E-2 Base A Base B
Plant name
Centiana bulgarica G . cruciata G. punctatu
E-1 E-2 J1
5-2 Substance V Substance VI Substance VII VP-2 VP-3 Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown TJnknown
Q. punctata G. asclepiadea C . asclepiadea G. punctata C . punctata Erythraea celztaurium Plantago notata P. albicana Erythrae centaurium E . centaurium Jasminum fruticans J . fruticans Menyanthes trifoliata M . trifoliata M . trifoliata Valeriam stolonifera V . stolonifera Anthocleista rhizophoroides Qentiana asclepiadea G. asclepiadea Qentiana sp. Qentiana sp. Gentiana sp. Skytanthus acutus S. acutus Swertia japonica Tecoma stana Verbascum songaricum
157-160
72 106 260 143-144

oil
249-252 240 189-191 Picrate, mp 125-127
197 197 197 194 140 137 61 61 178 178 199 199 138 138 138 200 200 169 86 86 142 142 142 166 33 193 39 164
(205,207). Work with S. acutus in vitro gave a labeled product from [2-14C]rnevalonate (208). Skytanthine is therefore derived from a terpenoid precursor. Similar results were subsequently reported by Waller and co-workers (209); [2-14C]mevalonatewas incorporated, but [2-14C]lysinewas not. Different specific activities of the skytanthines from different plant parts were observed both from feeding labeled mevalonate and labeled methionine. The latter was shown to be a specific precursor of the N-methyl group (209).
8.
487
A further complication was also uncovered, for considerable randomization of the label in the monoterpene terminal carbon atoms was observed in 3-year-old plants, yet essentially no randomization was found in experiments with 1.3-year-old plants (209). I n the biosynthesis of iridoids (124, 210-214) and indole alkaloids (201),randomization of label is consistently observed. Some of these problems have been discussed by Appel (215), who considers that multiple labeling must have occurred in order to have labeled the methyl group, C-9. Much of this work on skytanthines has been summarized by Marini-Bettolo ( 6 ) .
B. ALKALOIDS OF T. stuns
A more extensive study of the biosynthesis of the alkaloids of Tecoma stuns, has been carried out by Gross and co-workers (216). [2-I4C]Acetate and [2-14C]mevaIonate each labeled the alkaloids %skytanthine (8), tecostanine (16), tecomine (13), and boschniakine (44).[2-14C]Acetate was also incorporated into A5-dehydroskytanthine (28). The monoterpenoid nature of these alkaloids is therefore established. The N-methyl groups in 8, 28, 13,and 44 were derived from methionine. Neither loganin (57), uniformly labeled, nor actinidine (3) were incorporated into these alkaloids. Thus, the branching point for the formation of the skytanthine-type alkaloids occurs at a stage prior to formation of loganin, and the oxidation of the piperidine ring to a pyridine ring is not reversible. Uniformly-labeled &skytanthine (8), however, gave rise to moderate incorporation into tecostanine (16) and tecomine (13),but almost no incorporation into 44 or 28. N-Normethylskytanthine (47), on the other hand, gave excellent incorporation into tecostanine, moderate incorporation into 13 and 8, but very low incorporation into 44 (216).
C. ACTINIDINE (3) AND
THE
Vuleriuna ALKALOID 38
The biosynthesis of actinidine was first studied by Waller and COworkers (217),who demonstrated that it was not derived from lysine, aspartic acid, or quinolinic acid, but rather by a monoterpene route. Thus, [2-14C]acetate,[2-14C]mevaIonate(116), and [1 -14C]geranylpyrophosphate (117) were each incorporated into actindine in Actinidiu polygumu. [2-14C]Mevalonatelabeled actinidine (3)to the extent of 0.12% after only 24 hours, indicating the quite rapid alkaloid formation in this plant.
488
G E O F F R E Y A. CORDELL
Experiments by Gross and co-workers (57)with Valeriana o#cinalis demonstrated that [2-14C]mevalonate was an effective precursor of both actinidine and the quaternary alkaloid 38 t o the extent of 0.1 and 0.47%, respectively. Phenylalanine was not a precursor of the phenyl ring in 38, but tyrosine was found to be incorporated. Uniformlylabeled actinidine (3) was also incorporated into 38.
CH3 H O, C H x
'WIII
Hs
Hs
Hr Hr CO,H
Gy ./
\
0
CH,
116
CH3
117
N '
118
0 = degraded, active
4 ' 'OH
H0''''''B7
A = degraded, inactive
, \ \ "
0 Glu
HY% CH,
CO&H3
0
66 120
OGlu
CO,R
51 119
\ o
3
Glu 0
0
121
R=OH R =H
R = CH3
R =H
D. GEENTIANINE (62)
The incorporation of glycine into a number of terpenoid-derived was administered alkaloids has been observed (201).When [2-14C]glycine to young Gentiana asclepiadea plants (182) labeled gentianine was produced (182). Degradation and isolation indicated the labeling of gentianine as shown in 118. This labeling corresponds to a biosynthesis from [2J4C]acetate, but in the formation of acetate, current theories suggest that labeling should be a t the 1 position of acetate (218). Clearly there is much to learn about the utilization of glycine in terpine biosynthesis. Further work by the Bulgarian group (219)was aimed a t evaluating the role of pyruvate in gentianine biosynthesis. Neither [l-14C]pyruvatenor [ 1-l4C]formatewas incorporated. It was mentioned previouly that both gentiopicroside (66) and swertiamarin (65) are in vitro precursors of gentianaine (220, 221). It is therefore pertinent to comment on some aspects of the biosynthesis of gentiopicroside. A number of labeled mevalonates have been shown to be precursors (124,212-214,221-223). Experiments with [4-3H,2-14C](4R)and (4s)-mevalonates (116) indicated that as expected the 48-
8.
489
protons were lost and only one 4R-proton was retained. This tritium was located a t the ring junction hydrogen as indicated by conversion t o a tritiumless gentianine (221). Similar experiments with [2-2H,2-14C](2R)- and (2s)-mevalonates indicated that the tritium was lost from the 2S-labeled species and approximately half of the tritium from the 2R-labeled species. There was no tritium loss between loganic acid (119) and gentiopicroside, and subsequent work deduced that most of the tritium was a t C-7 (224). Loganin (51) (220,221)and loganic acid (221,223)are also excellent precursors of 66. [5,9-3H, 3,7,1l-14C]Loganic acid was incorporated into 66 with loss of half the tritium label (221, 223)) so that oxidation is regiospecific. Sweroside (120) is also a precursor of gentiopicroside (225, 226). More recently an iridoid gentioside (121) was isolated from three Gentiana species (227) and shown to be a precursor of gentiopicroside and, by implication, of gentianine.
E. GENTIOFLAVINE (85)
The novel monoterpene alkaloid gentioflavine was investigated by the Bulgarian group (142, 194, 228). [l-14C]Geraniol (122) and [1-14C]linalool (123) were each incorporated. Degradation of the labeled gentioflavine indicated that the activity was specifically a t the aldehyde group, thereby demonstrating the monoterpene derivation of gentioflavine (194). It was also demonstrated that a t least some of the biosynthetic reactions of the alkaloids may be reversible. Feeding uniformly labeled gentiopicroside to G. asclepiadea gave a 23% incorpora-
CH,
A
123
CH,
tion into gentioflavine (228).Previously, however, it had been demonstrated that gentioflavine was also a precursor of gentianine, gentianidine (79), and possibly gentianadine (74) (229). Labeled gentioflavine was not incorporated into gentiopicroside (228); hence, another route not involving gentiopicroside must exist for the conversion of 85 to 62. Experiments using 14C0, indicated that labeling of the alkaloids appeared in gentioflavine before gentianine (229). The biosynthetic data for the monoterpene alkaloids are summarized in Table IV.
TABLE IV INCORPORATION DATA FOR MONOTERPENE ALKALOIDS

Incorporationa Alkaloid precursor Actinidine [2-14C]acetate [2-14C]aspartate [2-14C]lysine [2-'4C]mevalonate
[ l-14C]geranyl pyrophosphate
Plant
%
0.04 0 0 0.17 0.47 0.06 0
Reference
[2,3,5,7-'4C4]quinolinicacid Boschniakine [' 4CImethionine Tecoma stans [2 - 4C]acetate T . stans [2-14C]mevalonate T . stans [U-3H]loganin T . stans [U-3H]N-normethylskytanthine T . stans [U-3H16-skytanthine T . stans [U-3H]actinidine T. stans A'-Dehydroskytanthine [14C]methionine Skytanthus acuttu [2-14C]lysine S. acutw [2-14C]mevalonate S. acutus A5-Dehydroskytanthine ['4C]rnethionine Tecoma stans [2- 14C]ace tate T . stans [2- 4C]mevalonate T . stans [W3HJloganin T . stans [U-3H IN-normethylskytanthine T . stans [U-3H1G-sl~ytanthine T . stans [U-3H]actinidine T . stans Gentianadine [U-'4C]gentioflavine Gentiana asclepiadea [U-'4C]gentioflavine G. asclepiadea Gentianine 1 4 ~ 0 , G . asclepiadea [14C]formate G. asclepiadea [ l-14C]acetate G . asclepiadea [2-14C]acetate G. asclepiadea [2-14C]glycine G. asclepiadea [I-"%Tpyruvate G. asclepiadea [2-'*C]mevalonate G . asclepiadea. [U 4C]gentioflavine G. aactepiadea
~
Actinidia polygama A . polygama A . polygama A . polyrJamu Valeriana oscinalis A . polygama A . polygama
21 7 217 21 7 21 7 57 21 7 21 7 216 216 216 21 6 216 216 216 209 209 209 216 21 6 21 6 216 21 6 216 216 229 229 220 220 199 119 182 219 182 194, 228, 229 229 194 194 228
L L
L
0 0
0 0 4.0 0 0.2
L L L
0 0.03 0.04 0
NG NG NG 0
L
NG NG 0 NG NC
Gentioflavine
1 4 ~ 0 ,
[ 1 -14C]geraniol [ 1-14C]nerol
[U-'4C]gentiopicroside
Gentiana asclepiadea G. asclepiadea G. asclepiadea 0. aaclepiadea
NG 3 . 0 3 . 0 2.3
490
TABLE I V (conrinued)
Incorporationa Alkaloid precursor Skytanthine [2-'4C]acet.ate [2-'*C]mevalonate Plant
%
0
Reference
Skgtanthw aeulus
S. acutw
L L 0
(~TZ
S. acutus S. acutus
a-Skytanthine [14C]methionine [2-'4C]lysine [2-'4C]mevalonate 8-Skytanthine ['4C]methionine [2-l4C]1ysine [2-14C]mevalonate 6-Skytanthine [14C]methionine [2-14C]acetate [2-14C]mevalonate [U-3H]loganin [U-3H]N-normethylskytanthine [U-3H]G-skytanthine [U-3H]actinidine Tecomine [14C]methionine [2-'4C]acetate [2-'4C]mevalonate [U-3H]loganin
vitro)
6, 206, 208 6 , 205, 207 208 6 , 205, 20 7
Skytanthus acutils S . acutus S. acutus Skytanthus acutus S. acutus S . aeutus

Tecoma stuns T . stam T . stans T . stuns T . stans T . stuns T. stans
4 . 0 0 0.17 10.0 0 0.2

1.1
209 209 209 209 209 209 216 216 216 21 6 216 21 6 21 6 216 216 216 216 216 21 6 21 6 216 216 216 216 216 216 216 57 57 57 57
L L
0 0.1 0.9 0
Tecoma stuns T . stuns T . stuns T . stuns [U-3H]N-normethylskytanthine T . stuns [U-3H]G-skytanthine T . slam T . stuns [U-3H]actinidine Tecoma stuns T , stuns T . stans T . stuns T . stam T . stuns T . stam Valeriana oflcinalis
0.2 L L
0 0.1 0.1 0
Tecostanine [ 4C]methionine [2-14C]acetate [2-'4C]mevalonate [U-3H]loganin [U-3H]N-normethylskytanthine [U-3H]6-skytanthine [U-3H]actinidine

Valeliana alkaloid (38) [Z'4C]mevaIonate [ U-'4C]phenylalanine [2-'4C]tyrosine [U-3H]actinidine
a
0.6 L L
0
1.4
0.6 0
0.1 0 0.02 0.04
v. oflcinali.9 v. oficinalis
V. oficicinalis
L = low incorporation; NG = not given.
491
492
GEOFFREY A. CORDELL
F. BIOGENESIS
It was mentioned in the introduction t o this chapter that much of the stimulation of interest in these alkaloids came as a result of the general interest in the iridoids and indole alkaloids following the proposals of Thomas ( 2 ) and Wenkert ( 3 ) . The biogenesis of the monoterpene alkaloids, a frequently discussed topic ( 1 , 10, 11, 14, 15, 44, 48, 57, 81, 84, 86,112, 125,137, 141,148), is intimately entwined with the biosynthesis of the iridoids and secoiridoids. It is therefore pertinent a t this point to summarize briefly some of the results and biosynthetic schemes developed in this area that are applicable to the monoterpene alkaloids. A scheme for the formation of the iridoids and secoiridoids from geraniol is shown in Scheme 1 1 . The scheme highlights some of the potential precursors of the monoterpene alkaloids, and each of these is + )-Mevalonic acid (116) is sequentially discussed sequentially. (R)-( phosphorylated to 5-phosphomevalonic acid and 5-phosphomevalonic
124
125
OPP ,CHa
'1$".
/
Hr
126
"'Hs
,
4 2 5
CH,OPP
117 R = PP 122 R = H
CH,OPP
127
SCHEME 11
$
CHO
f-
&LH,OH CH20H CH, Hr 131
rc--
6
I
493
CH,OH
CHaOPP
CH3
CH, Hr 132
I
Skytanthines
COaR
154
CH3 OGlu 128 R = CH3 137 R = H
Hr
C H O
y2R
X o + HO-
@
OGlu
139
C -
51
OGlu 129 R = CH, 130 R = H
HCH2
120
I-
65
---+
Monoterpem alkaloids
SCHEME 11 (conrinued)
acid (124). Trans elimination (230,231)affords isopentyl pyrophosphate, which undergoes enzyme-mediated stereoselective loss of the pro-4S hydrogen (232) and stereoselective addition of hydrogen t o the re side of the double bond (233)to produce dimethylallyl pyrophosphate (234). Stereoselective loss of the pro-48 (in mevalonate) proton (221,223,230, 235,236) from isopentyl pyrophosphate (125) in the couplingproduces elimination reaction with dimethylallyl pyrophosphate (126) geranyl pyrophosphate (117) in which both pro-4S hydrogens of
494
GEOFFREY A. CORDELL
mevalonate have been lost, and this has been confirmed using doublylabeled mevalonates into loganin (51) and loganic acid (119) (221, 223). After trans-cis isomerization of the 2,3 double bond in geranyl pyrophosphate (97) to give neryl pyrophosphate (127),cyclization and formation of the cyclopentanol ring occurs. I n the case of the iridoids and indole alkaloids thus far studied, this cyclization is stereospecifically cis and proceeds with retention of both hydrogen atoms as indicated. Steps after the cyclization and prior to the formation of deoxyloganin (128) are still in some doubt. Deoxyloganin is a precursor of loganin (237) and a number of secoiridoids (224,238-240),and it has been demonstrated that hydroxylation of deoxyloganin is stereospecific (225). The derivation of loganin (124, 222, 241) and secologanin (129) (242) from [2-14C]mevalonate is well established, as is their formation from variously labeled geraniols (222,235,242-244). Loganin is a precursor of secologanin, (245) secologanic acid (130) (242,246),and a number of other secoiridoids (220,221,223,224,239,247-249). Secologanin has been demonstrated to be a precursor of a number of secoiridoids (249) and this route from loganin to the secoiridoids as well as another route have been investigated by Inouye and co-workers (249). Returning to a point in the biosynthesis scheme where the cyclopentane ring has just formed, we observe that a number of possible routes exist, depending upon the various stages of oxidation of the two alcohol functions and the methyl group in 131. I n the formation of the Skytanthus alkaloids, oxidation of the two alcohol functions occurs to the dialdehyde 132, with subsequent condensation with ammonia. The labeling a t C-9 of skytanthine (4) from [2-14C]mevalonate (209) would imply a randomization a t some point and would involve an unlikely oxidation, subsequent reduction of the methyl group, and N-methylation with methionine. Oxidation after condensation with ammonia, rather than reduction, affords actinidine (3).Several oxidized actinidine/skytanthine-typealkaloids are known; for example, tecostanine (16)and tecostidine (17),in which one of the ring methyl groups has been hydroxylated. This oxidation may occur after formation of the nucleus, but it seems more probable that a hydroxydialdehyde such as 133 is involved. It has been implied that the series of compounds, actinidine, tecostidine, boschniakine (44), boschniakinic acid (18), and 4-noractinidine (48) forms a neat biosynthetic oxidative series. No experiments t o prove or disprove this concept have been reported. However, it seems more likely that oxidation of the C-8 methyl group of nerol occurs after formation of the cyclopentane ring and before alkaloid formation; thus,
8.
495
species of the type 133 and 134 and other highly oxidized species should be involved. A number of hydroxyskytanthines are known (see earlier), and again the problem arises as to their derivation from an alkaloid (skytanthine) precursor or an oxidized monoterpene. No experiments in this area have been reported. In the case of hydroxyskytanthines I and I1 (22 and 21), it may be that hydroxylation is part of the initial cyclization reaction giving 135 and 136, which subsequently condense with ammonia and are reduced.
133
135
136
I n the hydroxyskytanthines, where the ring junction is hydroxylated, it seems more probable that a preformed alkaloid is a precursor. Cantleyine (50) was shown to be an artifact in Cantleya corniculata formed by ammonia addition to loganin (51) (77). In a similar manner, boschniakinic acid (18) may be derived by ammonia condensation with deoxyloganic acid (137) (224). Decarboxylation of 18 leads to 4-noractinidine (48) as noted previously. A number of 4-noriridoids are also known, so that again this presents an alternative biosynthetic route. The same comments apply to the formation of venoterpine (52), which may or may not be derived from the carboxylic acid corresponding to cantleyine (138).
50 138
R = CH, R =H
140
Cleavage of the cyclopentane ring of loganin probably proceeds via 10-hydroxyloganin (139) (250) to give secologanin (129).The subsequent elaborations of secologanin by condensation and rearrangement are numerous and are evidenced by the wide array of known secoiridoids. This structure diversification is almost matched in the monoterpene
496
GEOFFREY A. CORDELL
alkaloids. There are six basic structure types of monoterpene alkaloids derived from the secoiridoid skeleton thus far isolated. In simple terms, we can envisage the formation of these skeleta as occurring from the ester trialdehyde 140 by selective condensation reactions. This highly functionalized compound is merely the hydrolysed version of secologanin, and it serves a useful purpose in analyzing the probable biosynthetic origin of the monoterpene alkaloids. For the purpose of deriving the alkaloid skeleta, we will consider five different orientations of this unit in condensation with ammonia. These orientations are depicted in Scheme 12 and the primary alkaloid from this orientation is shown. This, of course, is only a schematic representation, and we must look more carefully if we are t o discern the probable iridoid precursors of each alkaloid. Unlike the indole alkaloids where structure diversification takes place a t the alkaloid level, it appears that structure modification in the monoterpene alkaloids occurs a t the iridoid level.
0
/*
Fontaphilline (69)
Gentianine (62)
Jasminine (96) SCHEME 12. Biogenesis of the monoterpene alkaloids.
497
Gentiatibetine (100)
CHO COaCH3 NH3
H
Bakankoside (60)
'02CH3
&
CH$
c o 2 P C H 3 N Pedicularine (110)
CHO CHO NH3
rH0\
CH3
104
SCHEME 12 (continued)
498
GEOFFREY A. CORDELL
As was mentioned previously, both gentiopicroside (66) and swertiamarin (65) condense readily with ammonia to give gentianine, thereby delineating a possible biosynthetic precursor. Swertoside (119) is at a lower oxidation state than 66, and condensation of the lactone ring with ammonia would give bakankoside (60) having the absolute stereochemistry indicated. Similar condensation with ammonia in the lactone ring of kingiside (142) would give jasminine (96). A study of the iridoids of Gentiana punctata (195) afforded a new secoiridoid, gentioflavoside (142). Treatment with aqueous ethanolic ammonia afforded gentioflavine (95)) but no details are available on the formation of 141. Condensation with ammonia in the lactol ring of
$
H CH, OGlu
CH3
o
142
141 a-CH3 146 /I-CH,
secologanin (129), reduction of the aldehyde, and condensation with p-hydroxybenzoic acid would lead t o fontaphilline (69). The biogenesis of gentiatibetine (100) presents an interesting problem. One possibility is shown in Scheme 12, but a second possibility also exists involving a compound such as tetrahydroantirride (143) as a precursor as shown in Scheme 13. The probable biogenesis of enicoflavine (90) and gentiocrucine (87) was mentioned previously. It is pertinent t o note here the isolation of erythrocentaurin (144) from E. hyssopifolium and Swertia lawii (251),since this is another compound derived from swertiamarin (65) via the lactonic dialdehyde 145.
OGlu 143
CH,
OGlu
100
SCHEME
13
499
The existence of optical antipodes of some of the alkaloids also presents a slight problem. In most instances, this is due to the opposite configuration a t C-8. There are several examples of iridoids in which both C-8 epimers occur naturally, and the situation with kingiside (141) (252) and epikingiside (146) has been studied by Inouyes group (253), who demonstrated the operation of two separate routes for the formation of these substances.
144
145
147
For the situation in the series of a monoterpene alkaloids that are formed from a monoterpene prior to iridoid formation, we must envisage a different biogenesis in which 8-epiiridoidal (147) is an intermediate. It was suggested by Inouye (253) that d- and Z-citronellals are the intermediates which give rise to the opposite C-8 configurations. Citronella1 (148) was not a precursor of the indole alkaloids (254).Extensive further work is required before the subtle details of the biosynthesis of both the monoterpene alkaloids and the iridoids are clarified.
IV. Pharmacology of the Monoterpene Alkaloids

The original interest in the plants of the Gentianaceae arose because of the widespread use of gentian in Europe (255). At the turn of the century, Gentiana spp. were current in no less than twenty pharmacopaeias, the important species being Gentiana lutea, G. purpurea, G. punctata, and G. panonica (256).A discussion of the pharmacological action of these alkaloids concludes this review.
500
GEOFFREY A. CORDELL
A. ACTINIDINE (3)
Actinidia polygama is a potent feline attractant (257), and the principal alkaloid, actinidine, has been shown to exhibit strong attractant activity for several species of Felidae, including the cat, lion, tiger, and leopard (54).Actinidine also has a marked effect on the EEG of the cat (258, 259), since during EEG flattening positive spikes were distinctly observed similar to those obtained with acetylcholine. A number of side effects have been observed (260). The pharmacology of actinidine has been reviewed (261).
B. TECOMINE (13) AND TECOSTANINE (16)

The leaves of various Tecoma species have enjoyed a wide and prolonged use by the natives of Mexico in the control of diabetes ( 3 7 , 3 8 ) . Tecomine citrate and tecostanine hydrochloride were examined for hypoglycemic activity in rabbits (262,263). Both alkaloids showed activity at 20 mg/kg intravenously and 50 mg/kg orally in fasting animals. In depancreatized rabbits, the compounds were ineffective. Alloxan-induced hyperglycemia was effectively reduced a t a dose of 20 mg/kg. Problems associated with the stability of tecomine have also been examined (43). C. GENTIANADINE (74) Gentianadine, isolated from several Gentiana sp., exhibits hypothermic (264,265),hypotensive (264),antiinflammatory (264,266),and muscular relaxant actions (264).It is only very mildly toxic and shows no effect on behavior or growth on prolonged administration (267).
D. GENTIANINE (42)
Gentianine is the most widely studied of the Gentiana alkaloids. Preliminary examination indicated no antifungal or antibacterial effects. LOW toxicity was observed, and gentianine exhibits a central nervous system stimulant action, but in higher doses has a paralyzing a d o n . A t a dose of 90 mk/kg, gentianine reduces formalin-induced rat hind leg swelling (187,268), and i t was suggested to act via the nervous and hypophyseal system (268).Simihr to gentianadine (74), i t exerts hypotensive, antiinflammatory, and muscular relaxant actions but is more
50 1
effective than 74. Prolonged administration of gentianine had no effect on behavior or growth (267). A comparative study (266)of the antiinflammatory activity of several pyridine alkaloids indicated that the most active alkaloids (25 mg/kg, oral) were oliverine and gentianine, followed by gentianadine and gentianamine (81) .
TABLE V PRARMALOGICAL PROPERTIES OF MONOTERPENE ALKALOIDS Alkaloid Actinidine (37) Pharmaoological action Feline attractant Affects cholinergic neurons of the brain Sialogogue No feline attraction Vomiting (on parenteral administration) Olfactory reflex stimulation Anesthetic potentiator Decreased motility Hypothermic Hypotensive action Antiinflammatory effect Muscular relaxant No effect on behavior or growth Antiinflammatory Low antiinflammatory effect Central nervous system Hypothermic Hypotensive Antiinflammatory Antihistamine Decreases motility Muscular relaxant No effect on growth or behavior No antibacterial action No antimalarial activity No antifungal activity No antiamoebic effect Antiinflammatory Nicotine-like conditioned discriminated avoidance behavior Sedative action Toxicity No psychotropic effects Hypoglycemic Hypoglycemic Cholinesterase inhibitor Reference
Gentianadine (74)
Gentianamine (81) Gentianaine (92) Gentianine (62)
Oliverine Skytanthine (4)
54, 55, 62 258, 259 260 260 260 27 3 264 264, 265 264, 265 264 264, 266 265 267 266, 274 266, 274 271 264, 265 264, 271 268 113 264, 265 264, 265 264, 267 2 71 175 271 179 266 272 272 272 272 262, 263 262, 263 65
Tecomine (13) Tecostanine (16) Valerianu alkaloid (38)
502
GEOFFREY A. CORDELL
The principal folkloric reputation of Gentiana sp. is as a tonic, which may be related to the hypotensive and muscle-relaxant activity of gentianine (264). Enicostema littorale is used in Indian traditional medicine as an antimalarial (269),and this activity was traced to the chloroform-soluble alkaloid fraction (270). Gentianine, the principal alkaloid, had no affect on Ptasmodium gallinaceum (271) or P . berghei (179),so that the activity must be attributed to some other constituent. Further work (265)on gentianine and gentianadine has indicated that both compounds exhibit central muscle-weakening action, inhibition of provoked aggression, and analgesic potentiating effects.
E. SKYTANTHINE (4)
The pharmacology of the skytanthine alkaloids has been investigated by Gatti and Marotta (272).It exhibits no curare-like action but does induce tremors. It has a facilitating effect on the rate of acquisition of avoidance behavior (like nicotine). Low toxicity was observed. Its pharmacology has been reviewed ( 6 ) . Valerian preparations are widely used as a mild sedative. The major alkaloid (38) is a highly active inhibitor of cholinesterase activity but shows less acetylcholinesterase activity (65).The available data on the pharmacology of the isolated alkaloids are summarized in Table V.
V. Summary
The monoterpene alkaloids are a comparatively undeveloped group of alkaloids. Although some forty alkaloids have been isolated and characterized mostly from pharmacologically active plants, more data are required to evaluate their potential usefulness.
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182. N. Marekov, M. Arnaudov, and S. Popov, Dokl. Bolg. Akad. Nauk 23, 169 (1970); C A 73, 11391m (1970). 183. S. Shibata, M. Fujita, and H. Igeta, J. Pharm. Soc. Jpn. 77, 116 (1957). 184. V. N. Karpovich, T r . Leningr. Khim.-Farm. Inst. 12, 201 (1960); C A 57, 12631i (1962). 185. I. K. Nikitina, Tr. Leningr. Khim.-Farm. Inst. 21, 159 (1967); C A 69, 74504p (1968). 186. N. V. Kurinnaya, Nek. Yopr. Farm. 197 (1956); C A 53, 20695d (1959). 187. C.-Y. Sung, H.-C. Chi, and K.-T. Liu, Sheng Li Hsueh Pa0 22, 201 (1958); C A 53, 134156 (1959). 188. N. V. Kurinnaya, Aptechn. Delo 3 (4), 15 (19.54);C A 49, 2677g (1955). 189. D. S. Sargazakov, Izv. Akad. Nauk Kirg. SSR, Ser. Estestv. Tekh. Nauk 2, 103 (1960); C A 55, 202i (1961). 190. I. T. Eskin, Tr. Inst. Kraev. Eksp. Med., Akad. Nauk. Kirg. SSR No. 2, 75 (1959); C A 54, 12490e (1960). Espan. Fis. Quim., Ser. B 60, 607 191. C. Casanova and A. G. Gonzalez, An. R . SOC. (1964). 192. Kyoshin Seiyaku Co., Japanese Pat. 18,497 (1962); C A 59, P7323e (1963). 193. Yamashiro Pharmaceutical Co., Japanese Pat. 10,925 (1967);C A 68, 16138r (1968). 194. N. Marekov, L. Mondeshki, and M. Arnaudov, Dokl. Bolg. Akad. Nauk 23, 803 (1970); C A 74, 20401n (1971). 195. S. S. Popov and N. L. Marekov, Chem. Ind. (London) 655 (1971). 196. A. Abdusamatov and S. Yu. Yunusov, Khirn. Prir. Soedin. 4, 392 (1968). 197. N. Marekov, N. Mollov, and S. Popov, C . R. Acad. Bulg. Sci. 18, 999 (1965). 198. S. M. Khafagy and H. K . Mnajed, Acta Pharm. Suec. 5 , 135 (1968); C A 69, 80134j (1968). 199. S. S. Popov, N. Marekov, and P. Panov, Dokl. Bolg. Akad. Nauk 23, 1247 (1970). 200. Yu. I. Kornievskii, A. G. Nikolaeva, and K. E. Koreshchuk, Farm. Zh. (Kiev)27, 81 (1972); C A 77, 2804d (1972). 201. G. A. Cordell, Lloydia 37, 219 (1974). 202. D. V. Banthorpe, B. V. Charlwood, and M. J. 0. Francis, Chem. Rev. 72, 115 (1972). 203. A. R. Battersby, Bwchem. J. 111, 26P (1969). 204. I. D. Spenser, Compr. Biochern. 20, 231 (1968). 205. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Gazz. Chim. Ital. 94, 1356 (1964). 206. G. B. Marini-Bettolo, i n Biologenesi delle Sostanze Naturali, Corso Estivo di Chimica, Academia Nazionale Dei Lincei ( 1962). 207. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Rend. Acead. Naz. Yo (Quaranta)16-17, 89 (1965-6); C A 68, I0289u (1968). 208. M. A. Luchetti, Ann. Ist. Super. Sanita 1, 563 (1965); C A 65, 9349a (1966). 209. H. Auda, H. R. Juneja, E. J. Eisenbraun, G. R. Waller, W. R. Kays, and H. H. Appel, J. Am. Chem. Soc. 89, 2476 (1967). 210. D. A. Yeowell and H. Schmid, Ezperientiu 20, 250 (1964). 211. J. E. S. Hiini, H. Hilterband, H. Schmid, D. Groger, S. Johne, and K. Mothes, Ezperientia 22, 656 (1966). 212. C. J. Coscia and R. Guarnaccia, J. Am. Chem. SOC. 89, 1280 (1967). 213. H. Inouye, S. Ueda, and Y. Nakamura, Tet. Lett. 3221 (1967). 214. H. Inouye, S. Ueda, and Y. Nakamura, Chem. Pharm. Bull. 18, 2043 (1970). 215. H. H. Appel, Scientia 35, 128 (1968); C A 71, 124733b (1969). 216. D. Gross, W. Berg, and H. R. Schutte, Biochem. Physiol. Pflanz. 163, 576 (1972).
8. MONOTERPENE
ALKALOIDS
509
217. H. Auda, G. R. Waller, and E. J. Eisenbraum, J. Biol. Chem. 242, 4157 (1967). 218. S. P. J. Shah and L. J. Rogers, Biochem. J. 114, 395 (1969), and references therein. 219. N. Marekov, S. Popov, and G. Georgiev, C. R . Acad. Bulq. Sci. 19, 827 (1966); CA 66, 8845j (1967). . 220. D. Groger and P. Simchen, 2. Naturforsch., Teil B 24, 356 (1969). 221. C. J. Coscia, L. Botta, and G. Rocco, Arch. Biochem. Bwphys. 136, 498 (1970). 222. C. J. Cosia and R. Guarnaccia, Chem. Commun. 138 (1968). 91, 204 (1969). 223. R. Guarnaccia, L. Botta, and C. J. Coscia J . Am. Chem. SOC. 224. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Tet. Lett. 2351 (1969). 225. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 3453 (1968). 226. H. Inouye, S. Ueda and Y. Takeda, Chem. Pharm. Bull. 19, 587 (1971). 227. S. Popov and N. Marekov, Phytochemistry 10, 3077 (1971). 228. N. Marekov, S. Popov, and M. Arnaudov, Dokl. Bolg. Akad. Nauk 23, 955 (1970). 229. N. Marekov, N. Arnaudov, and S. Popov, Dokl. Bolq. Akad. Nauk 23, 81 (1970). 230- G. Popjak and J. W. Cornforth, Biochem. J. 101, 553 (1966). 231. J. W. Cornforth, R. H. Cornforth, G. Popjak, and L. Vengoyan, J. BioL Chepn. 241, 3970 (1966). 232. J. W. Cornforth, R. H. Cornforth, C. Donninger. and G. Popjak, Proc. R.. Y o c . , Ser. B 163,492 (1966). 233. K. Clifford, J. W. Cornforth, R . Mallaby. and G. T .Phillips, Chens. Concmun. 1599 (1971). 234. B. W. Agranoff, H. Eggerer, V. Henning, and F. Lynen, J. Biol. Chem. 235, 326 (1960). 235. A. R. Battersby, T. C. Byrne, R. S. Kapil, J.A. Martin, T. G. Payne,D. Arigoni, and P. Loew, Chem. Commun. 951 (1968). 236. M. J. 0. Francis, D. V. Banthorpe, and G. N. J. LePatourel, Nature (London) 228, 1005 (1970). 237. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun.826 (1970). 238. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 3351 (1970). 239. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 4073 (1971). 240. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Chem. Pharm. BUCI. 20, 1287 (1972). 241. R . Guarnaccia, L. Botta, and C. J. Coscia, J. Am. Chem. SOC. 94, 6098 (1970). 93, 5320 (1971). 242. R. Guarnaccia and C. J. Coscia, J. Am. Chem. SOC. 243. A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Martin, and A. 0. Plunkett, Chem. Commun. 812 (1966). 244. A. R. Battersby, E. 8. Hall, and R. Southgate, J. Chem. SOC. C 721 (1969). C 1187 (1969). 245. A. R. Battersby, A. R. Burnett, and P. G. Parsons, J. Chem. SOC. 96, 7079 (1974). 246. R. Guarnaccia, L. Botta, and C. J. Coscia, J . Am. Chem. SOC. 247. H. Inouye, S. Ueda, and Y. Takeda, 2. Naturforsch., Teil B 24, 1666 (1969). 248. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 4069 (1971). 249. H. Inouye, S. Ueda, K. Inoue, and Y. Takeda, Chem. Pharm. Bull. 22, 676 (1974). 250. L.-F. Tietze, J. Am. Chem. SOC. 96, 946 (1974). 251. S. Ghosal, A. K. Singh, P. V. Sharma, and R. K. Chaudhuri, J. Pharm. Sci. 63, 944 (1974). 252. H. Inouye, T. Yoshida, S. Tobita, K. Tanaka, and T. Nishioka, Tetrahedron 30, 201 (1974). 253. H. Inouye, in Pharmacognosy and Phytoehemistry (H. Wagner and L. Horhammer, eds.), p. 290ff. Springer-Verlag, Berlin and New York, 1971. 254. A. R. Battersby, S. H. Brown, and T. G. Payne, Chem. Commun. 827 (1970). Bessler, and P. Schroeder, Pharmazie 20, 16 (1965). 255. M. Luckner, 0.
510
GEOFFREY A. CORDELL
256. R. Osterwalder, Schweiz. Apoth.-Ztp. 58, 201 (1920). (1970). 257. T. Sakan, Tampakushitsu Kakusan Koso 12, 2 (1967); C A 73, 4 2 3 5 1 ~ 258. N. Yoshii, K. Hano, and Y. Suzuki, Folia Psychiatr. Neurol. Japan 17, 335 (1964); CA 61, 13376g (1964). 259. N. Yoshii, K. Hano, and Y. Suzuki, Med. J . Osaka Univ. 15, 155 (1964); CA 65, 6138g (1966). 260. T. Khayashi, Rejleksy Golovn. Mozga, Dokl. Mezhdunur. Konf., 1963 431 (1965); CA 67, 10216x (1967). 261. K. Hano, Tampakushitsu Kakusan Koso 12, 10 (1967); C A 73, 43432s (1970). 262. Y. Hammouda, A. K. Rashid, and M. S. Amer, J. Pharm. Pharmacol. 16,833 (1964). 263. Y. Hammouda and M. S. Amer, J . Pharm. Sci. 55, 1452 (1966). 264. F. S. Sadritdinov and N. Tulyaganov, Farmakol. Alkaloidov Glikozidov 128 (1967); C A 70, 2217v (1969). 265. N. Tulaganov, B. L. Danilevskll, and F. S. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 148 (1971); C A 78, 6 6 9 1 8 ~ (1973). 266. F . Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 146 (1971); C A 78, Serdechnykh 79634b (1973). 267. N. Tulyaganov, S. A. Gamiyants, and F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 153 (1971); C A 78, 9 2 4 8 1 ~ (1973). 268. H.-C. Chi, K.-T. Liu, and C.-Y. Sung, Sheng Li Hsueh Pa0 23, 151 (1959); C A 57. 11821g (1962). 269. C. J. Bamber, Plants of the Punjab, p. 157, 1916. 270. P. N. Natarajan and S. Prasad, Planta Med. 22, 42 (1972). 271. E. Steinegger and T. Weibel, Pharm. Acta Helw. 26, 333 (1951). 272. G. L. Gatti and M. Marotta, Ann. Ist. Super. Sanita 2, 29 (1965); C A 65, 14293e (1966). 273. T. Hayashi, Abh. Dsch. Akad. W w s . Berlin, KZ. Med. 101 (1966); C A 67, 2 0 2 4 7 ~ (1967). 274. F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 151 (1971); C A 78, 92480t (1973).
---CHAPTER 9-
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE

R. H. F. MANSKE
University of Waterloo Waterloo, Ontario, Canada
I. Introduction ........................................................ 1 1 . Plants and their Contained Alkaloids ................................... References ..........................................................
511 511 551
I. Introduction
Much of the data collected in this chapter was gleaned from Chemical Abstracts and is so indicated by listing a Chemical Abstracts reference, although such a reference is often included for the convenience of readers even where the original was available. Many of the alkaloids are of structural types not treated in recent chapters of earlier volumes. This chapter is supplementary to Volume XV, Chapter 6.
1 1 . Plants and Their Contained Alkaloids 1. Adaline (XV,264)*
The ketone Me(CH,), .CO -CH=CH,, prepared from the corresponding carbinol by Jones oxidation, was cyclized with methoxyethylene to the dehydropyran 1, which upon acid hydrolysis generated the ketoaldehyde Me(CH,),CO(CH,),CHO, which underwent a Mannich reaction with p-ketoglutaric acid and ammonium chloride to give ( f )-adaline (2) (1).
* The roman numeral followed by an arabic number refers to volume number and page where the subject of the heading has been treated in previous volumes.
512
R. H. F. MANSKE
2. Alphonsea ventricosa Hook. f. et Thorns. (Anonaceae) Norglaucine and glaucine (2). 3. Ancistrocladus hamatus Gilg. ( A . vahlii Am.) (Ancistrocladaceae; Dipterocarpaceae) (XIV,509; XV,265) Hamatine (3)(CZ5Hz9O4N; mp 250-252'C). It is phenolic and its 0methyl derivative is enantiomeric with 0-methylancistrocladine (3).
OMe
I
GMe
I
OMe Me
4. Ancistrocladus heyneanus Wall.

- 149.7')
(XIV,509; XV,265)
The new alkaloid ancistrocladidine (Cz5Nz,0,N; mp 245-247OC; has structure 4 as determined on spectral evidence (4).
OMe
OH
Me
4
5. Aniba duckei Kostermans (Lauraceae) (XI,496)
CI3Hl1O4N; mp 243-245'C), The new 3-pyridyl ketone, duckeine (5; was isolated from this plant. 2,6,4'-Trihydroxy-4-methoxybenzophenone was also isolated ( 5 ) .
OH
OH
5
9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
513
6. Ankorine
(X,546; XIII,191)
The structure of this alkaloid has been revised to 6 on the evidence that none of the four possible synthetic racemic forms represented by the earlier structure are identical with the natural alkaloid (6).
HO
CH2
6
CH,OH
7. Antirrhinum spp. (Scrophulariaceae) (XIV,511) Some tertiary bases or mixtures of bases were present in A . molle L., A . mollissimum (Pau)Rothm., and A . hispanicum Chav. One of these bases was identified as 4-methyl-2,6-naphthyridine and another was given the impossible formula C,,H,,O,N, (7).
8. Ariocarpus agavioides (Castaii.) E. F. Anders
(Neogomesia agavioides Castaii.) (XIV,512; XV,293)

This plant yielded N,N-dimethyl-4-hydroxy-3-methoxyphenethylamine and the related Pelecyphora aselliformis Ehrenb. yielded N , N dimethyl-3-hydroxy-4,5-dimethoxyphenethylamine. I n addition, seven previously known alkaloids were isolated from these plants ( 8 ) .
9. Aristolochia argentina Griseb. (Aristolochiaceae) (XII,460)
A reexamination of this plant has yielded four closely related lactones

(7, mp 271C; 8, mp 275C; 9, mp 247-25OOC; 10, mp 225C) which
7 8 9 10
R=R=H
R = H , R = OMe
R = Me,R= H R = Me, R = OMe
514
R. H . F. MANSKE
presumably arise from catabolism of preformed aporphines or analogous bases. They were separated on a column of silicic acid (9). 10. Atalantia monophylla Correa (Rutaceae) (XII,500; XIV,513; xV,267) Atalaphyllinine (C,,H,,O,N; mp 205-207C). Its structure (11) was indicated by an examination of its spectra and was confirmed by conversion to bicycloatalaphylline (10).
11
11. Azureocereus ayacuchensis Johns. (Cactaceae) Though mescaline was absent there was a comparative abundance of tyramine (0.135y0)in this cactus (11). 12. Bathiorhamnus cryptophorw (H. Perrier) R. Capuron (Rhamnaceae) Two new piperidine-type alkaloids were isolated and their structures indicated by spectral examination and confirmed in part by chemical reactions; cryptophorine (C,,H,,ON; mp l l & l l S C ; [a]578 - 61'; 0acetyl-, mp 103-104'c) (12); cryptophorinine (C,,H,,O,N; [a]578 - 68") (13). The former yielded an octahydro derivative (14) upon catalytic reduction which upon catalytic dehydrogenation generated a pyridine derivative (12).
Me0
12
Me
R
W
OH
14
R = n-C,,H,,
9.
515
13. BauereZZa baueri (Schott) Engler (Rutaceae) Melicopidine (mp 121-122"C) and acronycine (mp 172-175C) (13). 14. Bruguiera cylindrica L. (Rhizophoraceae) (XIII,353) Brugine, an unusual tropeine, was isolated from the stems and bark
(14)15. Burkea africana Hook. (Leguminosae) Tetrahydroharman, harman, and harmalan (15). 16. Gadia eZZisiana Baker (Leguminosae) (IX,206) This very toxic plant yielded some fifteen bases, three of which were identified as multiflorine, 13-hydroxylupanine, and its pyrrole carboxylic ester calpurnine (16).The last is highly toxic to mice and fish (17). 17. Camptothecine (XII,464; XIV,515; XV,269)
Yet another synthesis of this alkaloid has been reported in which 2,5-pyridine dicarboxylic acid was the starting material, being converted into 15 in 85% yield in three steps. Subsequent steps involved several convergent routes which gave, as a late intermediate, compound 16. The ingenuity shown in the choice of reactions was equaled only in the experimental skill necessary to bring them about, even though only 300 mg of dl-camptothecine was obtained (18).
5
COaH
15
0
16
18. Cannabis satiwa L. (Urticaceae)
This much investigated plant has now yielded an alkaloid. Cannabisativine (C,,H,,O,N,; mp 167-168C; + 55.1") (17) was obtained from the roots and its structure was determined by an X-ray study of the base crystallized from acetone, Other spectral data are consistent
516
R. H. F. MANSKE
with this structure. Its presence in the leaves was indicated by thinlayer chromatography. It is the first example of a palustrine-type base from flowering plants (19).
19. Cathu edzdis Forskal (Celastraceae) (111,343; XI,489; XII,539; XV,280) The alkaloid previously named cathidine has been shown t o be a mixture comprised of a polyalcohol esterified with different amounts of acetic, benzoic, trimethoxybenzoic, evoninic, and nicotine acids. Reductive hydrolysis generates a polyalcohol which on acetylation provides an octaacetate identical with that similarly obtainable from evonine (20).
20. Cephalotaxus harringtoniana (Forbes) K. Koch (Cephalotaxaceae) (X,552; XIII,400; XIV,319; Xv,272)
The new alkaloid, desmethylcephalotaxinone (C,,H,,O,N; mp 102+ 213"), was given structure 18 on the basis of its spectra and on its partial synthesis from cephalotaxine (21).
107OC;
( 9
HO
0
18
21. Cephalotaxus harringtonia Sieb. et Zucc. The variety drupacea of this plant was found to yield the new alkaloids 1 1-hydroxycephalotaxine (C,,H,,O,N; [a]i6 - 139') (19) and drupacine (C,,H2,0,N; [ c z ] ; ~ - 137') (20) whose given structures were
9. ALKALOIDS UNCLASSIFIED A N D OF U N K N O W N STRUCTURE
517
determined largely by spectral methods and partly confirmed by hydrolysis of 19 to 20 (22).
!if ( 9
HO
Ho
19
OMe
20
bMl3
22. Clausena heptaphylla Wt. and Am. (Rutaceae) (XII,467; XII17274; XV,273)
Heptazolidine from the above plant was given structure 21, largely on the basis of spectral methods (23).
23. Clausena indica O h .
(XII,467; XIII,274; x V , 2 7 3 )
Indizoline (22), a new alkaloid, was isolated along with 3-methylcarbazole (24).
22
24. Clitocybe fasciculata Bigelow
(Lepista caespitosa (Brosadola) Singer) (Agaricaceae)

This fungus proved to be rich in alkaloids yielding 2.4Yo7the major component being lepistine (C,,H,,O,N,, liquid, bp 140-150C/0.01 mm; B . HCl, mp 242C; B .HI, mp 250-253C; B.MeI, mp 198-199C). An
518
R. H. F. MANSKE
X-ray examination of the hydrobromide defined its structure (23)and other spectral properties are consonant therewith (25).
mco.MO
0
23
25. Cocculus laurifolius DC. (Menispermaceae) (X,406)
Three new dibenz(d,f )azonine alkaloids were reported-laurifonine (C,oH,,03N; perchlorate, mp 182-185OC, [elD 10) (24); laurifine (C,,H,,O,N, amorphous, [elD f 0) (25); and laurifinine (C1,HZ3O3N, perchlorate, mp 243-245OC) (26). The structures were arrived at by spectral studies and confirmed in part by interconversions (26).
OR
24
25
R R
26
=R = Me = H , R = Me R = Me, R = H
26. Cocculus carolinus DC.
(XII,468; XIII,325)
The new alkaloid carococculine (27) (C,,H,,O,N; mp 219-220C). The spectral properties of the alkaloid and of its 0-methyl and 0-acetyl derivatives indicated its structure. Its relation to other morphinane alkaloids is apparent (27).
MOoa
HO
OH
27
9.
519
27. Codonocarpus australis A. Cunn. (Phytolaccaceae) (xIV,579)
The structure of codonocarpine, previously reported, ha5 been confirmed and the N-methyl base (C,,H,,O,N,; mp 167-171C) (28) has been isolated from the plant and prepared from codonocarpine by N-methylation with formic acid followed by NBH reduction. Acetyl and other methyl derivatives have been described and extensive chemical degradations are reported (28).
b04
OH
OMe
28
28. Coryphantha calipensis H. Bravo (Cactaceae) (XII,468; XV,274)
Normacromerine, N-methyl-3,4-dimethoxyphenethylamine, and two new alkaloids, namely, ( - )-N-methyl-3,4-dimethoxy-~-methoxyphenethylamine and ( - ) - N,N-dimethyl-3,4-dimethoxy-~-methoxyphenethylamine. It is noted that the new alkaloids are /I-methoxy derivatives of macromerine (29).
29. Couroupita guianensis Aubl. (Myrtaceae)
Couroupitine A (C,,H,0,N2; mp 265-266C; [a],, f 0). Spectral examination was consistent with structure 29. A second base (mp > 340C; [.ID f 0; N-acetyl, mp 186C) of molecular weight 304 ( M + ) of unknown structure was also obtained (30).
29
30. Crotalaria assarnica Benth. (Leguminosae) (XII,247; XV,274)
Monocrotaline (31).
520
R. H. F. MANSKE
31. Crotalaria burhia Buch.-Ham.
(XII,247; XIV,522)
Crotalarine (30).Its structure was based on its alkaline hydrolysis and other chemical transformations (32).Another examination of the same plant yielded monocrotaline and an alkaloid, croburine (mp 167-1 68C). Hydrolysis of it generated retronecine and 2,3-dihydroxy-4-ethy1-2,3,4trimethylglutaric acid, also new. Structure 30 was also proposed (33).
30
32. Crotalaria maduronsis Wight
(XII,247; XIV,522)
Isocromadurine (C,,H,,O,N; mp 135-1 36C; [elk5 + 43.5"), isolated from the seeds of this plant, on alkaline hydrolysis generated retronecine and the symmetrical HO,C .CH(Me)C(OH)Me-CHMe .CO,H (mp 129130OC). Therefore its structure is 31 (34).
31
33. Crotalaria spp.
Seeds of C. leioloba Bartl. (C. ferruginea R. Grah.) yielded monocrotaline while those of C. tetragona Roxb. gave integerrimine and trichodesmine, two alkaloids previously isolated only from Senecio spp. (35). 34. Cryptocarya alba Auth? (Lauraceae) (X,577; XIII,403; XIV,522)
( + )-Reticdine was the only base isolated from the leaves and bark
(36).
9.
521
35. Daphniphyllum teijsmanii Zellinger (Euphorbiaceae) ( x , 5 5 6 ; XII,472; XV,41)
A new alkaloid, daphniteijsmanine (C30H4903N; mp 228-232"C), isolated from this plant was shown to have structure 32. Its mass spectrum was reminiscent of that of secodaphniphylline and other spectral data confirm the given structure. It was also possible t o transform secodaphniphylline via its N-acetyl derivative and borohydride reduction into the 0,hl-diacetyl derivative of daphniteijsmanine (37).
32
36. Daphniphyllum gracile (Auth. '2) (Euphorbiaceae) (X,556; XII,472; XV,42)
Five new alkaloids, daphnigracine (33), daphnigraciline (34), oxodaphnigracine (35), oxodaphnigraciline (36), and epioxodaphnigraciline (37) are reported. Spectral methods were the major tools in this consigning but daphnigraciline methiodide was converted into yuzurine methiodide (38).
33 34 35 36 37
R = OH, R' = CHMe,, Ra = H R = OH, R' = Et, Ra = H R = OH, R' = CHMe2, R2R2 = 0 R = OH, R' = Et, RaRa = 0 R = Et, R' = OH, R2Ra = O
522
R. H. F. MANSKE
37. Dendrobates histrionicus
(XIII,405; XV,277)
The frogs of the genus Dendrobates elaborate a series of toxins of importance in the study of neuromuscular transmission. The venom of D . histrionicus has yielded histrionicotoxin (38), its octahydro derivative (39), and its perhydro derivative (40). A synthesis of the last, the optically inactive form, had been achieved starting from the known compound 41. By a series of ingenious steps this was converted to 42, and after another four steps the perhydro compound was isolated by chromatography on silica (39). A more extensive examination of the alkaloids from the frog has yielded four analogs of histrionicotoxin whose structure (43) was determined by an X-ray analysis of its hydrochloride. A fifth compound, HTX-D [mp 231-232C (dec.)], corresponds in empirical formula to tetrahydrohistrionicotoxin but its mass spectrum indicates a different structural pattern (40).
CH2.R
0
41
42
43
38. Dendrobates pumilio
(XIII,405; XV,277)
Pumiliotoxin C, the toxic base isolated from the above-named frog, has been synthesized as its dl form. The starting material was a mixture of the known cis and trans forms of tetrahydro-1-indanone ( M ) ,the oxime of which generated a hydroquinolone. Further transformations,
9.
523
over ten in number and utilizing some novel reactions and skilful techniques, finally generated the dl base (45) with the correct stereo structure (41).
& ! &
0
Me
44
45
46
39. Dendrobine
(XII,475; XIII,406; XIV,525; Xv,277)
The total synthesis of this ( ) base has been reported. The starting material t o achieve this in twenty steps was the ketol 41, which by a series of standard reactions was converted to the ketolactam 47. Another series of reactions converted 47 into the enone 48 and subsequently into the hydroxyester 49 which on hydrolysis and lactonization generated ( k )-oxodendrobine (50, X = 0) and which was converted to (4 )dendrobine (50, X = H,) on Birch reduction (42). The biosynthesis of this alkaloid is consistent with its derivation from
:":;1*' fi0
Me
H
47
Me
48
0
49 50
524
R. H. F. MANSKE
mevalonate involving successive transformations t o farnesol, germacrane, and cadalane skeletons. Degradation of the labeled dendrobine appeared in the confirmed that the labeled carbon of [4-14C]mevalonate anticipated positions (43).
40. Dendrobium chrysanthum Wall. (Orchidaceae)
(XV,279)
Exhaustive spectral studies and a synthesis of ( ~fr)-trans-dendrochrysine obtained from this plant proved the structures of the cis and trans alkaloids (51). They were obtained only as viscous oils with [ a ] : , - 19" and with [a]i2 - 1 l 0 , respectively ( 4 4 ) .
IpJJ-j
N N
Me
I co I
CH=CH. Ph
51
41. Dendrobium crepidatum Lindl.
(XIV,525; Lv,297)
Crepidine (C18H2502N,mp 107-109"C, [a]$500-600 0 ) , crepidamine (C,,H,,O,N, mp 221C) [a]g4 - 82(MoH)), and dendrocrepine (C33H4403N, m p 158-163"C, [4]~~0-600 0) were isolated from this plant. An X-ray study of its methiodide showed that crepidine has structure 52. Crepidamine was shown to have structure 53 on the basis of a mass spectrum. Dendrocrepine, on the basis of a more elaborate spectral study, was given structure 54 (45, 46).
HO'
HO
Me
52
::a ;:f!i-3
I
Me
Me
c=o I
Me*-
53
54
42. Dendrobium nobile Lindl.
(XII,475; XIII,406; XIV,525; XV,279)
4-Hydroxydendroxine (55) and nobilomethylene (56) were isolated. Spectral methods were used in determining these structures and 56 was prepared from nobilinone (57) ( 4 7 ) .
9.
525
55
56
57
43. Desmodium cephalotes Wall. (Leguminosae) (XI,]1 ; XIII,406; XV,279) /3-Phenethylamine, salsolidine, hordenine, tyramine, candicine, choline, and several unidentified quaternary bases, many only in trace amounts (48). 44. Dolichothele sphaerica Britton et Rose (Cactaceae) (XIV,526) When selected precursors are presented to this plant i t generates unnatural alkaloids. When simultaneously given the lower homolog of histamine and isocaproic acid it produced 58, an analog of dolicotheline. Similarly, the aberrant alkaloid 59 was formed when 3-aminoethylpyrazole was fed (49).
HN
! l
CH, .NH .CO . CH2 .CH, .CHMe,

58
45. Dolichotele surculosa (Boed.) Buxb.
(XIV,526)
The four major alkaloids from the above-named plant were Nmethylphenethylamine, hordenine, N-methyltyramine, and synephrine. Four other plants of the genus, namely, D . longimamma (DC.) Br. et R., D . uberiformis (Zucc.) Br. et R., D . melaleuca (Kar.) Craig, and D . haumii (Boed.) Werd. et F. Buxb. were also examined. They were rich in alkaloids but the constituent bases differed essentially from those of Mammillaria and these differences appear to have taxonomic significance (50).
526
R. H. F. MANSKE
46. Doryphora sassafras Endl. (Monimiaceae) (XIV,228)
A total of eleven crystalline alkaloids was isolated from the bark of this plant. The four alkaloids from the nonphenolic fraction were liriodenine, doryanine, ( + )-isocorydine,and ( - )-anonaine. The phenolic fraction yielded ( + )-reticuline,corypalline, doryphornine (60) (mp 215217OC), and two bases, A (mp 169-171C) and B (mp 201-203"C, [a]z5 - 15.6'), not further examined. Extensive use was made of chromatography (51).
60
47. Erythrophleum chlorostachys Baill. (Leguminosae) (X,561; XII,533; XIV,528)
The structure of norerythrostachaldine (61) was established by LAH reduction to a tetrol (62) identical with one prepared from norerythro(52). stachamine (63)
R'
R = CHO. R' = CO, .CHa.CH, .NHMe R = CHSOH, R' = CH,.OH 63 R = C02Me, R' = CO,. CH,. CH, .NHMe
61 62
48. Erythrophleum ivorense A. Chevalier
(X,561; XII,533; XIV,528)
Two new variants of the cassaine-type alkaloids have been isolated from this plant. They are 3-(3-methylcrotonyl)cassaine(64) and 19hydroxycasesine (65) (53).
9.
527
64
65 66
R = CO.CH=CH,, R = M e R = H , R' = CHzOH R = H, R' = CO,Me, CO is -OH
49. Erythrophleum chlorostachys Baill. (x,561; XII,533; XIV,528) Norerythrostachamine, a new alkaloid (C,,H390,N, amorph.), was shown to have structure 66. The nonnitrogen fragment was identical with the NBH reduction product of erythrophlamic acid. In addition there were isolated cassaidine, cassamidine, norcassamidine, and a number of amides (54).
50. Erythroxylum monogynum Rox b. (Erythroxylaceae)
(XII,476; XIII,355) The 3,4,5-trimethoxybenzoyl and 3,4,5-trimethoxycinnamoy1 dewere isolated from the roots (55). rivatives of laH,5aH-tropen-3~~-01(67)
67
51. Eschscholtzidine (x,478; XII,371)
A synthesis of'this alkaloid by standard methods has been announced. The optically inactive base was characterized as its methiodide (mp 305OC) (56).
5 2 . Euxylophora paraensis Hub. (Rutaceae) (XII,477) 1 -Hydroxyrutaecarpine (68) (Cl8Hl3O2N3, mp 3 1 8-32OoC; O-methyl, mp 253C) was isolated. Its structure was derived from a spectral exa.mination and confirmed by a synthesis (57').
528
R. H. F. MANSKE
68
53. Fagara xanthoxyloides Lam. (Rutaceae) (XIV,530; XV,300) Another examination of this plant yielded the alkaloid fagaronine, a quaternary base (chloride, mp 200C, followed by solidification and remelting a t 26OoC) which proved to be an extremely active antileukemic (58).I t s proposed structure (69) was confirmed by a synthesis. The known compound 70 (R = H) was prepared by a new route and the hydroxyl was protected by the isopropyl group. Condensation of 70 ( R = Pr') with o-bromveratraldehyde and subsequent cyclization with sodamide in liquid ammonia followed in turn by reaction with dimethyl sulfate generated the 0-isopropyl ether of fagaronine methosdfate as well as the methosulfate of fagaronine (59).
P
Me0
O
NO2
OMe R
69
70
54. Fagopyrum esculentum Moench. (Polygonaceae)
The basic fraction obtained from buckwheat seed provided a crystalline base, fagomine (C,H,,03N; B .HCl, rno 176-177OC). Its structure (71) was arrived a t by an exhaustive spectral study and confirmed in part by chemical reactions (60).
71
9.
529
55. Gentiana sp. (Gentianaceae)
(XI,487; xV,282)
A new alkaloid (CloHllO,N, mp 208-210C, [a],, 0.8") has been isowas revealed by spectral lated from a Chinese gentian. Its structure (72) methods. Like a t least some other gentian alkaloids, i t may be an artifact (61).
H
72
56. Gymnocactus (Cactaceae)
Seven species of this genus were shown to contain predominantly known 8-arylethylamines along with traces of unidentified bases (62).
57. Haloxylon persicum Bunge ( H . ammodendron Bunge) (Chenopodiaceae) (XI1,480; XIV,534)
Anabasine was the major component of a total of 5.4y0 alkaloids in this plant. Traces of nicotine were also detected (63).
58. Haplamine
(IX,229; X,565; XII,480; XII1,408; XIV,534)
4-Hydroxy-6-methoxy-2-quinolinewas alkylated with Me,C= CH .CH,Br and the resulting mono-0-alkyl ether cyclized by reaction with dichlorodicyanobenzoquinone to yield haplamine ( 6 4 ) .It had been isolated from Haplophyllum perfora(mp 199C) (72a) tum Kar. et Kir. and the correct struction had been proposed (65).
59. Haplophyllum foliosum Vved. (Rutaceae) (IX,225; XV,284)
Folirninine, isolated from the aerial parts of the above plant, was given structure 72b on the basis of a spectral examination. Hydrogenation
530
R. H. F. MANSKE
generated a tetrahydro derivative (73) and reaction with methyl iodide gave 74 (66).
p-p:pJ
0 0 H
0
Me
72b
73
74
60. Haplophyllum perforatum Kar. et Kir.
(IX,229; XV,283)
The 7-isopentyloxy derivative of y-fagarine was isolated and prepared by the 0-alkylation of haplopine with Me,C=CH .CH,Cl. Its structure (75)was determined on the basis of spectral data. Hydrogenation generated the quinolinone 76 (67). Methylevoxine, a new alkaloid from this plant, is 77 as determined by spectral methods (68). Glycoperine (78) and haplophydine (79) were later isolated from this plant. Their structures are based on spectral data and upon the hydrolysis of 78 to haplopine and L-rhamnose (69, 7 0 ) .
?Me
OMe
Me$: CH. CHIO
J $ I J
OMe
75
Me,CH. C O z .CH,O
@ :
H
OMe
76
?Me
\ I
C .C H .CH,O
Me OMe I
77
OMe
R hO
* J
OMe
78
OCH,. CH: CMez

79
9.
531
61. Haplophyllum latifolium Kar. et Kir.
( x , 5 6 5 ; XIV,535)
I n addition to six unknown compounds the known skimmianine, haploperine, and dubamine were identified from this plant (71).
62. Hedera helix L. (Araliaceae)
The unusual occurrence and isolation of emetine from this plant has been reported (72).
63. Heimia salicifolia Link et Otto (Lythraceae) (X,566; XIV,525)
Abresoline (C,,H,,O,N, amorphous) was isolated in very low yield. Hydrolysis in the presence of alkali generated transferulic acid and the quinolizidol 80 so that its structure is 81. This was confirmed by a synthesis of its dihydro derivative (73).
9 , .
OMe
80
R=OH 81 R = M e 0 HO
64. Heimia salicifolia Link et Otto
(X,566; XIV,525)
I n addition to the known sinicuichine, cryogenine, and nesodine, there were isolated two new alkaloids, ALC-I (C,,H,,O,N, mp 335-345"c, + 115.6", [a]436 + 235") and ALC-2 (C2,H2g0,N, mp 309-310"C7 [a]589 + 72.3", [a]436 + 154.6") which were shown to be stereoisomers of lythrine. The former yielded a monomethyl ether melting a t 230233C and that of the latter melted at 235-237C ( 7 4 ) .
65. Hippodamine (XIV,518; XV,284)
An X-ray diffraction analysis of crystals of convergine hydrochloride, the N-oxide derivative of hippodamine, showed that it is 82 and consequently the structure of hippodamine is also known (75).
532
R. H. F. MANSKE
Me
82
66. Hydrastis canadensis L. (Ranunculaceae) (IV,87; IX,49; X,423)
Canadaline (C2,H230,N, mp 117-1 lSC, [.ID + 43O), a new alkaloid from this much investigated plant, was shown to have structure 83. Spectral examination and chemical manipulation served this purpose
(76)-
OMe
83
67. Indicaine
(XIII,417)
The alkaloid described as boschniakine was shown to be identical with the previously known indicaine (84) (76a).
84
68. Isoharringtonine
(XIV,SI9)
This alkaloid (85) is an ester of cephalotoxine, the acid component of which is dibasic, contains two asymmetric carbons, and is also a methyl ester. Methanolysis of the alkaloid generated a dimethyl ester that was
9.
ALKALOIDS UNCLASSIFIED A N D OF UNKNOWN STRUCTURE
533
shown, by a synthesis, to have the erythro configuration 86. This was achieved by hydroxylating the corresponding maleic acid with osmium tetroxide and hydrogen peroxide. Hydroxylation of the corresponding fumaric acid generated an acid of t,hreo configuration (77).
053)
0
H-85 86
69. Knightin deplanchei Vieill. (Proteaceae) (XV,287)
Two tropane alkaloids (87 and 88) were isolated. Their structures were determined by spectral methods (78).
Ph. COz
OR
'CH(0H)Ph R = CO.CH:CH.Ph R = H
87 88
70. Kreysigia rnulti$ora Reichb. (Liliaceae) (X,569; XII,483; XIII,146; XIV,268; XV,298) In addition to the alkaloids previously isolated from this plant there have been isolat,edthree new ones: ( - )-multifloramine (89) (C21H,505N, mp 209-2 12C) [a]g - 1og"), kreisiginone (90) (mp 193-1 94C)) and deacetylcolchicine. Methylation of 89 and of Aoramultine with diazomethane gave a mixture of kreisigine (91) and 0-niethylkreysigine (92). Spectral examination, culminated by a synthesis, confirmed the struct,ures and ascertained that of the previously known floramultine (93) ( 7 9 ) .Extensive biosynthetic studies showed that these homoaporphines arise from 1 -phenethylisoquinolines, specifically from automnaline (94) labeled as shown (SO).
534
M @ H e0
,
/
R. H. F. MANSKE
Me ) s M e
Me0 H0
Me0
I'
OMe
89
90
Me0 Me0
HO
Me0
OMe
94
7 1 . Ii~yPrstrouniaindica L. (Lythraccae) (X,557)
A n carlicr structure for lagerine has been revised because the synthetic compound of t h a t struct lire was not identical with the alkaloid. O-l\letIiyllageriiie was compared spectrally with vertallirie (95) and rcuritten as 96 and lagcrinc as 97. A synthesis of 96 was achieved by a serics of rvactions in which thc ether bridge was built by Ullrrian condensation of the appropriate but rather complicated compounds (81).
R' H %\
Me0
R
95 96
97
R = O M e , R' = H R = H , R' = OMe R = H, R'= O H
9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
535
72. Leptorhabdos parvijlora Benth. ( L . benthumiana Walp.)
(Scrophulariaceae) The structure of t,he new alkaloid, leptorhabine (98), was determined by spectral methods and confirmed in part by permanganate oxidation to pyridine-3,4-dicarboxylic acid (82).
98
73. Lindera benzoin Meissn. (Benzoin aestivale Nees.) (Lauracea,e) (XIII,412; XV,287)
Laurotetanine was isolated (83).

74. Liriodendron tulipifera L. (Magnoliaceae) (XIV,227)
The leaves of this plant yielded lirinine N-oxide (99) and lirinine 0-methyl ether which was also obtained by reducing the AT-oxide to lirinine (100). Spectral methods were employed in the structural determination (84). I n addition to the known nonphenolic alkaloids (isoremerine, liriodenine, lysicamine) the new isolaureline (101) was also isolated. Its structure is based on spectral data (85).
M HO
H-O
HO
/ g r
\
OMe
\
OMe
99
\
OMe
100
101
7 5 . Lophophora diffusa (Croizat) H. Bravo (Cactaceae) (XII,488; xv,288)
O-Methylpellotine (102), an alkaloid not previously known to occur naturally, was isolated (86).
536
R. H. F. MANSKE
OMe
102
Me
76. Magnolia obovata Thunb. (Magnoliaceae) (X,407; XII,489; XIV,228)
In addition to the known bases, liriodenine, anonaine, glaucine, asimilobine, reticuline, and magnocurine, this plant yielded a new alkaloid, obovanine, whose st,ructure (103) was determined from its spectral data (87).
103
77. Mappia foetida Miers (Oliacinaceae)
In addition to the previously reported camptothecine (88, 89) this plant has yielded mappicine (C,,H,,O,N,, mp 251-252C). It forms a n acetyl derivative (mp 191-1 92C) and on exhaustive spectral examination proved to be a relative of comptothecine with structure 104. A partial synthesis from camptothecine was achieved (90).
Et .CHOH
104
78. Maytenus arbutifolia (A. Rich.) R. Wilczek (Celastraceae)
(XI,460; XIV,541; XV,Z89)

- 19") (105) was isoCelacinnine (C,,H,O,N,, mp 203-204"C, lated from this plant and also from Tripterygium wilfordii Hook.
9.
ALKALOIDS U N C L A S S I F I E D A N D O F U N K N O W N S T R U C T U R E
537
Spectral studies of it indicated structural features that were consonant with chemical degradations. It yielded a dihydro derivative (mp 172C) and vigorous acid hydrolysis generated spermidine. The isomeric celallocinnine (mp 172-173"c, [a]g5 -24) (106), also present in M . arbutifolia, differed from 105 in that the cinnamoyl group is cis oriented. Its dihydro derivative is identical with that of 105. Two analogous alkaloids isolated from T . wilfordii are celabenzine (C23H,902N3, mp 156-158"C, [a]i5 0 ) (107) and celafurine (C,,H,,O,N,, mp 154155OC, [a]g5 - 11") (108), whose structures were assigned on the evidence of spectral and chemical properties (91).
R
105 106 107 = tmm-Ph.CH:CH.CO, R '=H R = c-Ph.CH:CH.CO, R' = H R = P h . C O , R' = H
108
= 0:R'
= H
79. Melicope perspiczsinerva Merr. et Perry (Rutaceae)
(XIV,542)
In addition to a new flavone (melinervin) and other neutral compounds this plant yielded skimmianine, kokusaginine, ( )-platydesmine, and halfordinine (mp 150-152C) the last of which was shown t o be 6,7,8trimethoxydictamnine (92).
80. Murraya koenigii Spreng (Rutaceae) (XII,491; XIII,544; XIV,274,414; XV,290)
The new murrayacinine is given structure 109 on the basis of its (93). spectra and on a synthesis from 2-hydroxy-3-methylcarbazole
Me
109
538
81.
R. H. F. MANSKE
Jlyrrha octodecimguttata (XIV,518)
The report of the chemical study of the above Coccinellidae contains the isolation of a new alkaloid, myrrhine (C13H2,N,liquid) (110), and a review of the relationship that exists among the alkaloids that have been isoated from a number of arthropods, namely, coccinelline, convergine, hippodamine, and propyleine. The structure of 110 was confirmed by correlation with propyleine (precoccinelline) as well as by varied spectral studies. Coccinelline was shown to be biosynthesized via the polyacetate pathways. These alkaloids have been shown to be involved in the defensive behavior of the insects (94).
H
110
82. Oncinotis nitida Benth. (Apocynaceae) (XIII,415; XIV,546) Three new spermidine alkaloids have been isolated. The structural assignments are based on spectral studies and upon chemical degradation to known fragments. Oncinotine (111) (C,3H,50N,, oil, [.ID - 33"); neooncinotine (112),obtained only in admixture with 111; isooncinotine (112a) (C2,H,,0N3, mp 66-71C, [a],, - 37"). Acetyl and reduced derivatives as well as hydrolytic products were prepared (95). A synthesis of ( )-oncinotine was also achieved. Some fifteen steps were involved in which one of the starting substances was HO(CH,),CO,H. An isomer of oncinotine was shown to be present in the natural base (96).
G-yyJ
R O
111 112
R = (CH,),NH, R = (CH,),NH,
H
ll2a
9.
ALKALOIDS UNCLASSIFIED A N D OF UNKNOWN STRUCTURE
539
83. Opuntia clavata Eng. (Cactaceae)
M-Methyltyramine was isolated (97).

84. Pandaca calcarea (Pichon) Mgf. and
P. debrayi Mgf.
(Apocynaceae) (VIII,203; XI,147)

( - )-Apparicine and ( - )-dregamine, known alkaloids, and the new + 417') and pandine pandoline (C21H2s03N2, amorphous, [.ID (C21H,,03N,, mp 108-1 13C; [.ID 273") (98).
85. PassiJlora sp.
, . , P . decaisneana Traces of harman were detected in P . caerulea I Hyb., P. edulis Sims, P . foetida L., P . incarnata I , . , P. subpeltata? ( P . subulata Masf.), and P. warmingii Masf., but neither harmine, harmah e , harmol, nor harmalol could be detected (99).
86. Pauridiantha lyallii (Baker) Bremek. (Rubiaceae) (XIV,547)
Two new indole alkaloids lyaline (113) and lyadine (114) were isolated (100,101).
C0,Me
113 114
R = CH=CHg R = CH(0H)Me
87. Pelea barbigera Hillebr. (Melicope barbigera A. Gray) (Rutaceae) (IX,229; XIV,542)
Kokusaginine, isoplatydesmine (115), and eduline, which was regarded as an artifact (102).
Me
115
540
R . H. F. MANSKE
88. Penicillium oxalicum
The alkaloid oxaline (C,,H,,O,N,, mp 220C, [a];, - 45') is unique in a number of respects, as is evident upon an inspection of its structure (116) which was determined by X-ray methods. Spectral methods and particularly mass spectra are consonant with this structure (103,104).
116
89. Pergularia pallida Wight et Am. (Asclepiadaceae) (IX,518; XIII,425; XIV,562)
Three major alkaloids proved to be tylophorine, tylophorinidine, and O-methyltylophorinidine. Minor constituents proved to be 3,6,7trimethoxyphenanthroindolizine and one of uncertain structure with four methoxyls in the phenanthrene portion and an alcoholic hydroxyl a t C-14 (105).
90. Peripterygia marginata Loes. ( Pterocelastrus marginatus Baill.)
(Celastraceae) The alkaloid periphylline isolated from this plant has structure 117 as determined by spectral methods. Alkaline hydrolysis gave transcinnamic acid and alkali fusion of its tetrahydro derivative generated spermidine (106).
H
H
1I7
91. Petteria ramentacea Presl. (Leguminosae)
Cystine and its N-methyl derivative appeared in the early growth stages of this plant. Anagyrine and lupanine appeared later (107).
9.
ALKALOIDS UNCLASSIFIED A N D O F U N K N O W N STRUCTURE
541
92. Physochlaina alaica Korotkova (Solanaceae) (X,17) Physochlaine has structure 118 as shown by a spectral study. Atropine was also present (108),as were apohyoscine and 6-hydroxyatropine (109). A still later report recorded the presence of a new alkaloid (C,,H,,O,N, mp 105-106C) which was identified as the N-oxide of 6-hydroxyhyosciamine (110).
.CH,
0
-
-0Me
93. Pilocarpus microphyllus Stapf (Rutaceae) (111,206)
Pilosine and epipilosine were isolated (111). 94. Piper trichostachyon C. DC. (Piperaceae) (XIII,417; XIV,551)
A homolog of trichostachine from this plant (C,8H,,03N, mp 147149OC) was shown to have structure 119 (112).
11s
95. Podopetalum ormondii F. Muell. (Leguminosae) (IX,184,213) The alkaloid ( - )-podopetaline, originally isolated from Ormosia semicastrata Hance and named ormocastrine (113, I14), is the major alkaloid from the above-named plant. An X-ray study of its hydrobromide (C,,H,,N. HBr) elucidated its absolute structure (120) (114,115).
542
R. H. F. MANSKE
96. Poranthera corymbosa Brogn. (Euphorbiaceae) (XIV,551; XV,294)
The plant yielded porantherine, porantheridine, porant,hericine (121) (C,,H,,ON, amorphous [.ID - 20"; B.HBr, mp 308"C), O-acetylporanthericine (amorphous, [a],,+ 2"), porantheriline (C,,H,,O,N, mp 76-77C; [.ID + 87"), and porantherilidine (CzzH,302N, amorphous, [.ID -47"; B.HBr, mp 251-252C) (122). The structure of 122 was arrived a t on the basis of an X-ray study of its hydrobromide. Porantherline on hydrolysis generates acetic acid and an alcohol (mp 124-126C) which was shown to be enantiomeric with 121 a t the hydroxyl position (116).
H
Et
HO121
12%
97. Porantherine
(XIV,551; XV,294)
This tetracyclic base (123), whose structure was determined largely by X-ray analyses, has been synthesized. Not only was there involved a multitude of intermediates, new to chemistry, but the experimental skill was evidently of a high order. The sequence of reactions was based upon a retrosynthetic analysis involving five key intermediates which were obt,ained from the first reaction product 124 of the Grignard reagent derived from 5-chloro-Z-pentanone ethylene ketal with ethyl formate (1.27).
Me
123
124
9.
543
98. Prosopis nigra (Gris.) Hieron. (Leguminosae) (XI,12,492)
/3-Phenethylamine, harman, tryptamine, N-acetyltryptamine, and tyramine all separated in the order given from a column of alumina (118).
99. Prosopis spicigera L. (XI,492)
The new amino acid spicigerine was given structure 125 (219).
125
100. Ptelea trifoliata L. (Rutaceae) (XIII,417; XIV,553)
This much-investigated plant has yielded a new quaternary base, O-methylptelefolium (126) (220).Another examination of P . trifoliata subsp. pallida disclosed the presence of hydroxylunine and balfouridine (121).
OM0
126
101. Retama monosperma Boiss. (Genista monosperma Lam.) (Leguminosae) (IX,1 99 ; XV,276)
The subspecies rhodorrhizoides yielded d-sparteine, retamine, anagyrine, sophocarpine, a,nd traces of sophoridine, N-methylcytisine, cytisine, and sophoramine (122).
102. Retanilla ephedra Brogn. (Rhamnaceae) (XV,295)
The following were isolated and identified : boldine, norboldine, armepavine, norarmepavine, coclaurine, and N-methylcoclaurine, as well as two cyclopeptides-integerresine and crenatine A (223).
544
R. H. F. MANSKE
103. Ruta bracteosa DC. ( R .chalepensis L. (Rutaceae) (IX,224; XII,462; XIV,553; XV,283)
In addition to three furocoumarins this plant yielded rutamine (127) (124).
Me
127
104. Rutaceae
(XII,503; XIII,423; XV,292)
A number of plants of this family when examined for alkaloids and triterpenes yielded results of possible taxonomic significance.Araliopsis tabouensis AubrBv. et Pellegr. yielded ( -+- )-A'-methylplatydesminium ions, a second furoquinoline, and flindissol. Diphasia lclaineana Pierre yielded lupeol, evoxanthine, arborinine, and skimmianine. Teclea verdoorniuna Excell. et Mendonga yielded lupeol and exoxanthine (125).
105. Sceletium Alkaloids (IX,468; XIV,554; XV,296)
Three new alkaloids were isolated from S . namaguense (L.) Bolus in addition to other known bases and sceletium A,, whose structure (128) was revealed largely by spectral methods; A7-mesembrenone (129) (C,,H,,03N, oil) previously prepared from mesembrine ; N-formyltortuosamine (130)(C21H,,0,N,, oil); and sceletenone (131) (C,,H,,O,N, oil). S.stricturn (L.) Bolus also yielded a number of known alkaloids oil) and the new 41-O-demethylmesembrenone (132) (C,,H,,O,N, methylation of which generated mesembrenone (126).
128
129
9.
545
130
131 R = H 132 R = OMe
106. Sedum maximum Suter (Crassulaceae) (XI,462)
The alkaloids, sedamine, sedinine, and sedridine were identified in the alkaloid mixture which was present to the extent of 0.008 to 0.01% in the dry plant (127).
107. Senecio cineraria DC (Compositae) (XII,256)
Jacobine, senecionine, seneciphylline, and retrorsine (228).

108. Senecio erraticus Bertol. (XII,245,251; XV,297)
Three alkaloids of mp 229-231C, 221-222"C, ([a],,+ 1 l 0 ) , and 192193C were isolated. Apart from limited IR data no identities were suggested (229).
109. Senecio petasitis DC. (XII,245; XV,297)
The alkaloid from this plant on hydrolysis generated retronecine and isolinecic acid and in consequence its structure is 133,in full conformity with spectral data (230).
OH
Et ---fl--CH,--CH-$-Me
I
I
Me
?H
I co
co
0
133
546
R. H. F. MANSKE
110. Senecio swaziensis Compton (XII,245; XlII,400; XIV,537; XV,297)
Swazine (C,,H,,O,N, mp 165"C, [a],, - 103.5"), which had been isolated from the above-named species and also from S. barbellatus DC. (131),has been subjected to chemical degradation and to spectral study. Acid hydrolysis generated retrorsine and a spirodilactone (134). Of the possible structures that could be derived from the above fragments that represented by 135 is favored (132).
co
I
O J ' iMQC
CHz
134
135
111. Sida cardifolia L. (Malvaceae) (X,581)
/3-Phenethylamine, ephedrine, #-ephedrine, methyl ester of N,methyltryptophan, hypaphorine, vasicinone, vasicine, vasicinol, and liberal amounts of choline and betaine (133).
112. Skimmianine and y-Fagarine
(X,565; XlI,480; XV,284)
These alkaloids were found in the following species of Haplophyllum : H . schelkovnikovii Grossheim, H . villosum G. Don( ?), H . kowalenskyi (Auth?),and H . tenue (Auth?)(134).
113. Sophora a l o ~ o c u r ~ d L. e s (Leguminosae) (VII,258; IX,208; XIV,557; XV,298)
I n addition to the known sophoridine, sophoramine, sophocarpine, and aloperine there was isolated neosophoramine (C,,H,,ON,) which was regarded as the 5-epimer of sophoramine (135). Tricrotonyltetramine (136) (C,,H,,N,; mp 101-103C) was later reported as a constituent of this legume (136).
9.
ALKALOIDS UNCLASSXFIED AND OF UNKNOWN STRUCTURE
547
Me
jJ.-J.-.
Me
H H
136
Me
1 14. Sophora prodanii E. Anders
(IX,208; XIV,257)
Sparteine and cytisine (137).

115. Streptomyces Species N 337 (XIII,421)
The structure of the base from this Streptomyces, M. ich had been regarded previously as a pyrrolidine derivative, has been revised to ( E ,E ) - 2-pentadienyl-3,4,5,6-tetrahydrop yridine (137) (138).
137
116. Swainsona galegifolia R. Br. (S. coronillaefolia Salisb.) (Leguminosae) (X,581; XIV,558)
Spherophysine was identified as a constituent (139).

1 1 7. Syneilesis palmata Maxim. (Compositae) (XII,245)
Syneilesine (C,,H,,O,N; mp 195"C), a highly cytotoxic alkaloid, was shown to have structure 138. Aside from spectral studies, hydrolysis and
?H
I
H
, I
?H
I I
Et-CH-C-C
I co
I
Me
-C-Me
CO
I
I
138
548
R. H. F. MANSKE
hydrogenolysis gave critical information. Hydrolysis gave three new closely related lactones which confirmed the nature of the acid moiety. Hydrogenolysis generated dihydrodeoxysyneilesine- 11,14-olide (139) (mp 109C) which on hydrolysis also yielded three lactones and the necine, dihydrodesoxyotonecine (140) (140).
co
Me
139
Me
140
118. Talauma mexicana G. Don (Magnoliaceae) (VII,445; XIV,227) Liriodenine (141). 119. Teclea boiviniana (Baill.) H. Perrier (Evodia boiviniana Baill.) (Rutaceae) (XII,503; XIII,423 ; XV,292) Malicopine, tecleanthine, and evoxanthine, all known acridones, were isolated. In addition, this plant yielded 6-methoxytecleanthine (141) and 1,3,5-trimethoxy-lO-methylacridene (142) (142).
0
OMe
Me0
141
142
120. Teclea grandifolia Engl.
(XIII,423; XV,292)
Tecleanone (C,,H,SO,N; mp 190OC) was obtained in 0.00670 yield in the form of yellow crystals. Its structure (143) was determined largely from its mass spectrum and other spectral data. It bears a formal resemblance to tecleanthine in that it is the open form of a possible acridone ( 143).
9.
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
549
121. Teclea unifoliata Auth 1
(XXI,503; XIII,423; XV,292)
Maculine, skimmianine, and kokusaginine were separated from the alkaloid mixture which was obtained in 0.5y0(144).
122. Templetonia retusa (Vent.) R. Br. (Leguminosae) (IX,213)
A new alkaloid, ( - )-templetine (C20H35N3; mp 120-3 22OC;
[.ID
- 5 2 O ) , was isolated in 0.02y0 yield as well as the known ( - )-cytisine, ( - )-anagyrine, ( )-lupanine, and ( & )-piptanthine. Vigorous dehydration of it afforded ( - )-dehydropiptanthine (CZ6Hz3N3). Spectral
methods including an X-ray analysis indicated the complete stereo structure (144)of this alkaloid. Since this alkaloid has now been related to ( - )-ormosanine and t o (-)-panamine, it is possible to assign the correct stereo structure to those as well (145).
144
123. Trichocereus pachanoi Britten et Rose (Cactaceae) (XII,506; XV,298)
The presence of mescaline and 3-methoxytyramine was proved (146).

124. Tylophora cordifolia Thw. and T. JEava Trirnen (Asclepiadaceae) (IX,518; XIII,425; XIV,562; XV,298)
The former yielded tylophorinine and three unidentified alkaloids on a chromatogram. Similar examination of T .Java gave tylophorine and four unidentified alkaloids (147).
550
R. H. F. MANSKE
125. Tylophora indica Merrill (T. asthmatica) (IX,518; XIII,425; XIV,562)
A reexamination of the structure of tylophorinidine by an X-ray study of its methiodide diacetyl derivative confirmed it to be 145 (148).Other spectral methods are consonant with that structure (149).
OMe
145
126. Ulugbekia tschimganica (B. Fedtsch.) Zakirov (Boraginaceae) Uluganine from this plant has structure 146 (R determined by spectral methods (150).
=
trachelanthoyl) as
90.
CH(0H)Me
WaoR
146
127. Vaccinium (Cranberry) (Ericaceae)
A new alkaloid (mp 168-170C) was obtained from the leaves of a cranberry native to New Brunswick. Its structure (147) was determined almost exclusively by spectral methods and confirmed by a synthesis. Tryptamine was condensed under physiological conditions with glutardialdehyde and the condensation product reduced with NBH. The
147
9.
551
resulting base was methylated with methyl iodide in the presence of sodium amide and the 1-methyl base (147) was identical wit'h the natural product (151).
128. Zanthoxylum americanum Mill. (Rutaceae) (XII,478; XIV,530)
Nitidine and laurifoline were isolated from the root and stem bark as well as the coumarins xanthyletin and xanthoxyletin. The presence of chelerythrine, tembetarine, magnoflorine, and candicine was demonstrated. The root bark of Z . clava-herculis was shown to contain laurifoline, magnoflorine, tembetarine, and candicine (152).
129. Zanthoxylzcm arnottianum Maxim.
(X,423; XII,478; XIV,530)
I n addition to a host of neutral compounds and a quaternary isoquinoline derivative isolated as picrate (C,,H,GO,N+* C,H,O,N; ; mp 256-26O0C), this plant yielded dictamnine, robustine, and haplopine (153).
130. Zanthoxylum tsihanimposa H . Perr. (XII,506; XIII,427; XIV,530)
The bark of this plant yielded y-fagarine, skimmianine, and 11dihydrochelerythrinylacetone, as well as two further derivatives of chelerythrine which appear to be artifacts (154).
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554
R. H. I?. MANSKE
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9.
ALKALOIDS UNCLASSIFIED A N D O F U N K N O W N STRUCTURE
555
101. J. L. Pousset, J. Levesque, A. Cave, F. Picot, P. Potier, and R. R. paris, plants Med. Phytother. 8, 51 (1974); C A 81, 117054J (1974). 102. T.Higa and P. J. Scheuer, Phytochemistry 13, 1269 (1974); CA 81, 166385b (1974). 103. P. S. Steyn, Tetrahedron 26, 51 (1970). 104. D. W. Nagel, K. G. R. Pachler, P. S. Steyn, P. L. Wessels, G. Gafner, and G . J . Kruger, Chem. Commun. 1021 (1974). R ~cent. . 105. N.B.Mulchandani and S. R. Venkatachalam, India, A.E.C., Bhabha [Rep.] B.A.R.C.-764, 8 (1974); C A 82, 108862q (1975). 106. R. Hocquemiller, M. Leboeuf, B. C. Das, H. P. Husson, P. Potier, and A. Cave, C . R . Hebd. Seances Acud. Sci., Ser. C 278, 525 (1974); C A 80, 133673~ (1974). 107. E.Steinegger, Pharm. Acta Helv. 48, 517 (1973); C A 80, 575052 (1974). 108. R. T. Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim. Prir. Soedin. 415 (1974); C A 81, 152460k (1974). 109. R. T. Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim. Prir. Soedin. 416 (1974); C A 81, 166359~ (1974). 110. R. T. Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim. Prir. Soedin. 540 (1974); C A 82, 82957x (1975). 111. W. Loewe and K. H. Pook, Ann. 1476 (1973). 112. J. Singh, M. A. Potdar, C. K. Atal, and K. L. Dhar, Phytorhemistry 13,677 (1974); C A 81, 35577t (1974). 113. S. McLean, P . L. Lau, S. K. Cheng, and D. G. Murray, Can. J. Chem. 49, 1976 (1971). 114. S. McLean, M. L. Roy, H. J. Lin, and D. T. Chu, Can. J . Chem. 50, 1639 (1972). 115. M. F. Mackay, L. Satske, and A. M. Mathieson, Tetrahedron 31, 1295 (1975). 116. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and H. Suares, Aust. J. Chem. 27, 2025 (1974); C A 81, 120833t (1974). 117. E. J. Corey and R. D. Balanson, J. Am. Chem. SOC. 96, 6516 (1974). 118. G. A, Moro, M. N. Graziano, and J. D. Coussio, Phytochemistry 14, 827 (1975); CA 83, 93851e (1975). 119. K. Jewers, M. J. Nagler, K. A. Zirvi, F. Amir, and F. H. Cottee, Pahlavi Med. .J. 5 , 1 (1974); C A 81, 230973. (1974). 120. J. Reisch, G. W. Mirhom, J. Korosi, K. Szendrei, and I. Novak, Phytochemistry 12, 2552 (1973); C A 80, 12480w (1974). 121. K.Szendrei, I. Novak, M. Petz, J. Reisch, H. E. Bailey, and V. L. Bailey, LZoydia C A 80, 12510f (1974). 36, 333 (1973); 122. A. Morales Mendez, A. Gonzalez Gonzalez, and F. Diaz Rodriquex, Rev. Fac. Farm., Uniu. Los Andes 8, 77 (1971); C A 82, 121629~ (1975). 123. D.S. Bhakuni, C. Gonzalez, P. G. Sammes, and M. Silva, Rev. Latinoam. Quim. 5 , C A 82, 108803~ (1975). 158 (1974); 124. A.Gonzalez Gonzalez, R. Estevez Reyes, and E. DiazChico, An.Quim.70,281(1974); C A 81, 117048k (1974). C A 80,45650e (1974). 125. G. Wsterman, Biochem. Syst. 2, 153 (1973); 126. P. W.Jeffs, T. Caps, D. B. Johnson, J. M. Karle, N. H. Martin, and B. Rauckman, J . Org. Chem. 39, 2703 (1974). 127. S. Logar, N. Mesicek, M. Pcrpar, and E. Seles, Farm. Vestn. (Ljubljana) 25, 21 C A 82, 82916h (1975). (1974); 128. A. Klasek, V. A, Mnatsakanyan, and F. Santavy, Collect. Czech. Chem. Commun. 40, 2524 (1975): CA 83, 175453r (1975). 129. R. I. Gaiduk, M. V. Telezhenetskaya, and S. Yu. Yunusov, Khim. Prir. Soedin 414 (1974); C A 82,54167w (1975).
&.
556
R. H. F. MANSKE
130. A. Gonzalez Gonzalez, G. De la Fuente, and M. Reina, An. Quim. 69, 1343 (1973); CA 80, 96194s (1974). 131. C. G. Gordon-Gray, R. B. Wells, M. B. Hursthouse, S. Neidle, and T. P. Toube, Tet. Lett. 707 (1972). 132. C. G. Gordon-Gray and R. B. Wells, J . Chem.. Soc., Perkin Trans. 1 1556 (1974). 133. S. Ghosal, Phytochemistry 14, 830 (1975); CA 83, 93854h (1975). 134. L. Y. Isaev and I. A. Bessanova, Khim. Prir. Soedin. 815 (1974); C A 82, 121677~ (1975). 135. T. E. Monakhova, 0. N. Tolkachev, V. 8. Kabanov, M. E. Perelson, and N. F. Proskurnina, Khim. Prir. Soedin. 472 (1974); C A 82, 541764. (1975). 136. T. E. Monakhova, 0. N. Tolkachev, M. E. Perelson, V. S. Kabanov, and N. F. Proskurnina, Khim. Prir. Soedin. 752 (1974); CA 82, 1 2 1 6 6 6 ~ (1975). 137. N. Paslarasu and A. Badauta-Tocan, Farmacia (Bucharest) 21, 693 (1973); CA 81, 87965n (1974). 138. M. Onda, Y . Konda, G. Narimatsu, H. Tanaka, J. Awaya, and S. Omura, Chem. Phurm. Bull. 23, 2463 (1975); CA 84, 5213r (1976). 139. J. Steineger and G. Reuter, Pharmazie 28, 682 (1973); CA 80, 1 1 8 1 9 6 ~ (1974). 140. M. Hikichi and T. Furuya, Tet. Lett. 3657 (1974). 141. T. Kametani, H. Terasawa, M. Ihara, and J. Iriarte, Phytochemistry 14, 1884 (1975); C A 84, 2213e (1976). 142. J. Vaquette, M. 0. Cleriot, M. R. Paris, J. L. Pousset, A. Cave, and R. R. Paris, Plant. Med. Phytother. 8 , 57 (1974); CA 81, 60857s (1974). 143. A. C. Casey and A. Malhotra, Tet. Lett. 401 (1975). 144. J. Vaquette, J. L. Pousset, and A. Cave, Plant. Med. Phytother. 8, 72 (1974); CA 81, 6085911 (1974). 145. J. R. Cannon, J. R. Williams, J. F. Blount, and A. Brossi, Tet. Lett. 1683 (1974). 146. D. M. Crosby and J. L. McLaughlin, Lloydia 36, 416 (1974); C A 80, 68385m (1974). 147. J. D. Phillipson, L. Tezcan, and P. J. Hylands, Planta Med. 25, 301 (1974); CA 81, 117038g (1974). 148. V. K. Wadhawan, S. K. Sikka, and L. B. Mulchandani, India, A.E.C., Bhabha At. Res. Cent. [Rep.] B.A.R.C.-764, 6 (1974); CA 82, 171258n (1975). 149. N. B. Mulchandani, S. S. Iyer, and L. P. Badheka, India, A.E.C. Bhabba At. Res. Cent. [Rep.] B.A.R.C.-764, 3 (1974); C A 82, 171257m (1975). 150. M. A. Wasanova, U. A. Abdulaev, M. V. Telezhenskaya, and S. Yu. Yunusov, Khim. Prir. Soedin. 809 (1974); C A 82, 140349~ (1975). 151. K. Jankowski, S. Godin, and N. E. Cundasawmy, Can. J. Chem. 52, 2064 (1974); CA 81, 63831q (1974). 152. F. Fish, A. I. Gray, P. G. Waterman, and F. Donachie, Lloydia 38, 268 (1975); CA 83, 128689n (1975). 153. H. Ishii, K. Hosoya, T. Ishikawa, E. Ueda, and J. Haginiwa, Yakugaku Zasshi 94, 322 (1974); CA 81, 132753e (1974). 154. N. Decaudain, N. Kunesch, and J. Poisson, Phytochembtry 13, 505 (1974); C A 81, 74879n (1974).
SUBJECT INDEX
Abresoline, 531 Acacia, 43 2-Acetyltrop-2-ene, 87 N-Acetyltryptamine, 543 Acnistus, 62 Aconitum, 24, 58 Acronycine, 515 Actinidia argista, 440 Actinidia polygama, 440 Actinidine, 52, 433, 436, 441 Adaline, 5 11 Adiantifoline, 269, 297 Adenocarpus, 46 Adina cordifolia, 54 Agastachys odorata, 153 Agroclavine, 63 Ailanthus giraldii, 42 Ajrnalicine, 54 Aknadicine, 394 Aknadilactam, 394, 422 Aknadinine, 394 Alatamine, 218, 238 Alatolin, 242 Alchornea fioribunda, 48 Alchorneine, 48 Alchorneinone, 48 Alphonsea venfricosa, 512 Alstonia venenata, 448 Amanita Muscaria, 22 Ambrosia, 5 Ammodendron conollyi, 13, 45 Anabasine, 17, 25, 51 Anabasis aphylla, 13, 25 Anabasine, 529 Anagerine, 549 Anagyrine, 540, 543 Ancistrodadine, 512 Ancistrocladus hamatus, 5 12 Ancistrocladus heyneanus, 5 12
Ancistrocladus vahlii, 5 12 Androcymbine, 67, 69 9-Angelylretronecine, 5 1 Anhalidine, 25 Anhalonidine, 25 Anhydronupharamine, 185, 187 Aniba duckei, 512 Anisocycla grandidieri, 270, 291, 309 Anisodarnine, 91 Anisodas, 61 Anisodine, 91 Ankorine, 513 Anonaine, 526, 536 Anthocercis, 61 Anthocercis littorea, 154 Anthocercis tasmanica, 154 Anthocercis viscosa, 154 Anthocleisra procera, 453 Anthocleista rhizophoroides, 473 Anthranilic Acid, 14 Antirrhinum, 10 Antirrhinum hispanicum, 5 13 Anfirrhinum molie, 513 Antirrhinum mollissimum, 5 13 Apoatropine, 91, I04 Apparicine, 539 Aquilegia, 10 Araliopsis tabouensis, 544 Arborinine, 544 Arecoline, 65 Argemone, 32, 38 Ariocarpus agavioides, 5 13 Aristolochia argenrina, 513 Arrnepavine, 51, 267, 323 Armepavine, 543 Arornoline, 258 Asimilobine, 536 Aspergillus, 22 Aspidosperma, 54 Atalantia monophylla, 5 14 Atalaphylline, 5 14
557
558
SUBJECT INDEX
Atisine, 58 Atropa, 10, 12, 61 Atropa belladona, 93, 139, 146, 154, 162 Atropa martiana, 164 Atrophine, 104 Atropine, 89, 127, 162 Azureocercus ayacuchensis, 5 14 B
Bacillus subtilis, 309 Bakankoside, 450 Baluchistanamine, 307 Baptisia leucophia, 11 Bathiorhamnus cryptophorus, 5 14 Belarine, 257 Bellendena montana, 85, 153 Bellendine, 85 2a-Benzoyloxynortropan-3~-01,92 2a-Benzoyltropane, 86 2-Benzyltropanes, 86 Benzoin aestivale, 535 Berbamine, 41, 297, 309, 348 Berbamunine, 334 Berbenine, 297 Berberis, 33 Berberis baluchistanica, 280, 307 Berberis laurina, 257, 272 Berberis lycium, 297 Berberis petiolaris, 297 Berberis vulgaris, 309 Bhesa archboldiana, 5 1 Bisjatrorrhizine, 258 N,N-Bisnoraromoline, 258 Boemeria cylindrica, 64 Boehmeria platyphylla, 64 Boldine, 543 Boschniakine, 443, 532 Boschniaka rossica, 444 Boschniakinic Acid, 438 Brugmansia, 61 Bruguiera exaristata, 89, 153 Bruguiera sexangular, 89, 153 Bruguiera cylindrica, 5 15 Brugine, 515, 89 Bufotenine, 18 Bulbocapnine, 31 Burkea africana, 515 Buxenine-G, 60 Buxus, 61
C Cadalene, 524 Cadaverine, 16 Cadia ellisiana, 515 Calligonum, 25 Calpurnine, 5 15 Calycanthine, 51 Calycanthus, 53 Camptorrhiza, 69 Camprotheca acuminata, 55 Candicine, 65, 525 Camptothecine, 515, 536 Canadaline, 532 Cantlega corniculata, 447 Cantleyine, 446 Cancentrine, 260 Cannabis sativa, 515 Cannabisatarine, 515 Capsicum, 62 Carococculine, 5 18 Casimiroa, 19 Cassamine, 46 Cassine matabelica, 246 Cassinic Acid, 246 Cassinine, 246 Cassinopsis ilicifolia, 55 Castoramine, 191 Catharanthine, 54 Catharanthus, 54 Catha edulis, 216, 218, 516 Cathidine D, 217, 218, 220, 224, 516 Cathol, 225 Celabenzine, 537 Celacinnine, 219, 536 Celafurine, 537 Celullocinnine, 537 Celapagine, 218, 220 Celapanigine, 218, 220 Celapanine, 218, 220 Celapanol, 22 1 Celastrus angulatus. 246 Celastrus orbiculaius, 246 Celastrus panicufatus, 216, 218 Centaurium pulchella, 473 Centaurium spicatum, 477 Cephaelis, 57 Cephalotaxus harringtonia, 5 16 Cephalofoxine, 532 Cephaeamine, 394, 420 Cepharanoline, 261
SUBJECT INDEX
559
Cepharanthine, 261, 345 Cestrum, 62 Chelerythrine, 41 Chelidimerine, 261 Chelidonium majus, 261 Chondodent, 296, 371 Chondodendron toxicoferum, 295 Chondrucurine, 25 I , 296 Chondrofoline, 252, 374 Cinchona, 57 Cis-endodihydroisobellendine, 85 Clausena heptaphylla, 5 17 Clausena indica, 517 Claviceps, 22, 62 Clitogbe fascicutata, 5 17 Cocaine, 51, 162 a-Cocaine, 119, 147 p-Cocaine, 120, 147 Coccineline, 538 Cocculus, 33 Cocculus carolinus, 58 Cocculus laurifolius, 518 Coclaurine, 543 Cocsoline, 305 Cocsuline, 262, 270, 309 Cocsulinine, 305 Cocculus leaeba, 282 Cocculus pendulus, 262, 282, 305 Codonocarpine, 519 Colchicine, 67 Colchicurn, 69 Colpidium colpoda, 309 Colubrina asiatica, 275 Conessine, 60 Coniine, 17 Conium, 17, 23 Contarea, 57 Convergine, 538 Convolvulus, 61 Cordifoline, 54 Corydalis, 33 Corypalline, 526 Couroupita guianensis, 519 Couroupitine A , 519 Coryphantha calipensis, 5 19 Cremastosperma polyphlebum, 308 Crenatine 17, 543 Crepidamine, 524 Crepidine, 7 1 , 524 Cratalaria, 207, 237, 44
Crotalaria assamiea, 519 Crotalaria burhia, 520 Crotalaria ferruginea, 520 Crotalaria leioloba, 520 Crotalaria rnadurensis, 520 Crotalaria tetragona, 520 Crotalarine, 520 Croton, 48 Croton diaco, 49 Croton gabouga, 49 Croton salutaris, 32 Croton turumiquirensis, 49 Crotonosine, 48 Cryptocarya bowiei, 32, 64 Cryptospermine, 64 Cryogenine, 531 Cryptophorine, 514 Cryptophorinine, 5 14 Cularine, 33 Curine, 296 Cuscohygrine, 90, 153 Cuspidaline, 334 Cyclea barbata, 309 Cyclea peltata, 263, 209 Cycleacurine, 263 Cycleadrine, 264 Cycleahomine, 265 Cycleanine, 297, 375 Cycleanorine, 266 Cycleapeltine, 267 Cyclea sp. (?), 297 Cyclobuxine-D, 60 Cynadum wilfordii, 241 Cynanchum, 56, 64 Cyphomandea betacea, 154 Cystine, 540, 549 Cyphomandra, 61 Cytisine, 44, 547
D
Daphnandra micrantha, 271 Daphneteijasmanine, 52 1 Daphmigraciline, 521 Daphniphylline, 50 Daphniphyllum gracile, 521 Daphniphyllum teijsmanii, 521 Daphrigracine, 521 Darlingia darlingiana, 86, 153 Darlingia ferruginea, 86, 153
560
SUBJECT INDEX
Darlingine, 86 Datura, 12, 61 Datura alba, 154 Datura arborea, 154 Datura bernhardii, 154, 164 Datura candida, 154 Datura ceratocaula, 90, 141, 154 Datura cornigera, 142, 154 Datura discolor, 154 Datura fastuosa, 154 Datura ferox, 137, 154, 162 Dafura godronii, 154 Datura inermis, 144 Datura innoxia, 90, 138, 154, 162 Datura leichardtii, 154 Datura metel, 154 Datura meteloides, 140, 154 Datura myoporoides, 144 Datura pruinosa, 154 Datura sanguinea, 91, 140, 154 Datura sframonium, 93, 136, 140, 154, 162 Dafura suaveolens, 89, 154 Datura tatula, 144, 154 Dauricine, 320, 387 Dauricinoline, 267 Dauricoline, 268 Daurinoline, 297, 334 2-Deacetylevonine, 218, 237 Delavaine, 394, 408 Dehydrodeoxynupharidine, I85 Dehydroskytanthine, 440 Delphinium, 24, 58 N,N-Demethyl-3,4-dimethoxy &methoxyphenethylamine, 5 19 3-O-Demethylhernandifoline,394, 41 1 4'-O-Demethylmesembrenone, 544 Dendrobates histrionieus, 522 Dendrobates pumilio, 522 Dendrobium, 7 1 Dendrobium chrysanthum, 524 Dendrobium erepidatum, 524 Dendrobium nobile, 524 Dendrobine, 523 (* )-trans-Dendrochrysine, 524 Dendrocrepine, 524 4-Deoxyeuonyminol, 246 CDeoxyevonine, 218, 230 Deoxyharringtonine, 20 3-Deoxymayto1, 226 Deoxynupharidine, 181 Deoxyscopoline, 132
Dercetylcolchicinu, 532 0-Desmethyladiantifoline, 269 N '-Desmethyldauricine, 270 12'-O-Desmethyltrilobine, 270 Desmodium, 43 Desmodium cephalotes, 525 Diethoxythiobinupharidine, 200 Dicaine, 164 Dicentra, 33 Dicentra canadensis, 260 2,6-Dideacetylevonine, 218, 237 Dihydroerysodine, 38
6,6*-Dihydroxythio-binupharidine, 200 6,6'-Dihydroxythionuphlutine, 200 Diphasia klainiana, 544

0,O-Dimethylcurine, 374 0,N-Dimethylmicranthine, 271 N,N-Dimethyltryptamine, 18 Dipidax, 69 Dipsacus aureus, 448 3a,6P-DitigIoyloxytropan-7B-O I , 89 Dolichotele baumii, 525 Dolichotele longimamma, 525 Dolichotele melaleuca, 525 Dolichotele sphaerica, 525 Dolichotele surculosa, 525 Dolichotele uberiformis, 525 Doryanine, 526 Doryophora sassajias, 526 Doryphornine, 526 Dregamine, 539 Drimys, 72 Drupacine, 516 Dubamine, 531 Duboisia, 61 Duboisia hopwoodii, 154 Duboisia myoporoides, 153, 163 Duckeine, 5 12 Dunalia, 61 E Ecgonine, 162 Eduline, 539 Effirine, 262 Elymoclavine, 63 Emetine, 56, 531 Enicoflavine, 458 Enicostemma hyssopitfolia, 458 Enicostemma littorale, 453 Enonymine, 218. 239 Ephedra, IS
SUBJECT INDEX
561
Ephedrine, 15, 546 "-Ephedrine, 546 7-Epideoxynupharidine, 182, 199 Epinetrum villosum, 297 3-Epinuphamine, 185, 189, 1% Epinuphararnine, 194, 199, 21 1 Epioxodaphnigraciline, 521 Epipilosine, 541 Epistephamiersine, 394, 403 Epistephanine, 272, 297, 309 Equisetum, 20 Ergine, 63 Erginine, 63 Erythraea centaurium, 456 Erythrina, 23, 33, 48, 44 Erythrophleum, 46 Erythrophleum chlorosthehys, 526, 527 Erythrophleum ivorense, 526 Erythrophleum monogynum, 527 Erythroxylum coca, 153 Erythroxylum ellipticum, 93, 153 Erythroxylum monogynum, 92, 153 Eschscholtzia, 32 Eschscholtzidine, 527 Eschscholtzine, 33 Espinidine, 272 Espinine, 273 Ethoxythiobinupharidine, 200 Eudalene, 221 Euolalin, 241 Euonine, 218, 239 Euonymus Europaeits, 51 Euonyminol, 225, 231 Euonymus aiatus, 218 Euonymus europaeus, 216, 218 Euonymus sieboldianus, 217, 218 Euxylophora paraensis. 527 Evodia boiviniana, 548 Evonimine, 218 Evonine, 216, 218, 231, 516 Evonine Acid, 216, 229, 231 Evonoline, 218, 229 Evorine, 218 Evoxanthine, 544, 548 Evozine, 218, 237 F
Fagopyrum esculentum, 528 Fagrea fragrans, 474 Fangchinoline, 309 Farnesol, 524 Ferrugine, 86 Ferruginine, 86 Festuca, 66 Festucine, 65 Fetidine, 252 Ficus, 64 Fontanesia phillyroides, 454 Fontaphilline, 454 N-Forrnyltortuosamine, 544 Fritillaria, 69 Funiferine, 274 Funtumia, 60
G
Galanthamine, 67 Garrya, 58 Genista, 46 Genista monosperma, 543 Gentiabetine, 463 Gentialutine, 448 Gentiana angustifolia, 474 Gentiana asclepiadea, 449, 456 Gentiana axillaris, 474 Gentiana axillijlora, 474 Gentiana barbata, 474 Gentiana biebersteinii, 474 Gentiana bulgarica, 474 Gentiana caucasia, 473 Gentiana clusii, 474 Gentiana cruciata, 458 Gentiana decumbens, 474 Gentiana dinaerica, 474 Gentiana fetisowii, 474 Gentiana freyniana, 474 Gentiana greacilipes, 474 Gentiana kaufmanniana, 473 Gentiana lutea, 449 Gentiana macrophylla, 456 Gentiana olgue, 456 Genriana olivieri, 456, 457, 464 Genfiana pneumonanthe, 474 Gentiana punctata, 474 Gentiana purdomrii, 474 Gentiana purpurea, 474 Gentiana scabra. 474 Gentiana schistocaktx, 474 Gentiana septenfidea. 474
Fagara xanthoxyloides, 15. 528 SFagarine, 530, 546, 551 Fagaronine, 528 Fagomine, 528
562
Gentiana sino-ornata, 474 Gentiana spp,, 529 Gentiana straminea, 474 Gentiana tibetica, 463 Gentiana turkestanorum, 455, 457 Gentiana wirilowi, 475 Gentiana vvendenskyi, 475 Gentiana wutaiensis, 475 Gentianadine, 455 Gentianamine, 457 Gentianidine, 456 Gentianaine, 459 Gentianine, 52, 432, 452 Gentiocrucine, 458 Gentioflavine, 457 Germacrane, 524 Glaucine, 31, 512, 534 Gliotoxin, 22 Gloriosa, 69 Glycoperine, 530 Glymnocactus, 529
H Haemanthamine, 67 Halfordinine, 537 Haloxylon ammodendron, 529 Hamatine, 5 12 Haplamine, 529 Haploperine, 531 Haplophydine, 530 Haplophyllum latifolium, 53 I Haplophyllum kowalenskyi, 546 Haplophyllum perforatum, 529, 530 Haplophyllum schelkovnikovii, 546 Haplophyllum tenue, 546 Haplophyllum villosun, 546 Haplopine, 530, 551 Harmalan. 515 Harman, 25, 515, 539 Hasubanonine, 394, 398, 422, 427 Hedera helix, 531 Heimia salicifolia, 531 Heliosupine, 19 Heptazolidine, 517 Hernandifoline, 394, 410 Hernandine, 394, 412 Hernandoline, 394 Hernandolinol, 394, 413 Heteratisine, 58 Hippodamine, 531, 538
SUBJECT INDEX
Hippomane mancinelia, 49 Histamine, 19 Histidine, 14 Histrionicotoxin, 522 Holarrhena, 24, 60 Holophyllamine, 60 Homatropine, 162 Hornoaromoline, 309 Homoroia riparia. 49 Homostephanoline, 394 Hordenine, 14, 65, 525 Hydrastis canadensis, 532 19-Hydroxycassaine, 526 1 I-Hydroxycephalotaxine, 5 16 4-Hydroxydendroxine, 524 4-Hydroxyhygrinic Acid, 49 Hydroxylunine, 543 13-Hydroxylupanine, 5 15 1-Hydroxyrutaecarpine, 527 a-Hydroxyscopolamine, 91 Hydroxyskytanthine I, 439 6 '-H ydrox ythiobinupharidine, 200 6-Hydroxythionuphlutine B, 200 Hydroxywilfordic Acid, 217, 229 Hygrine, 16, 51, 71 Hymenocaridia, 48 Hymenoxys, 5 Hymenoxys acaulis, 13 Hymenoxys ivesiana, 13 Hymenoxys scaposa, 13 Hyoscyamine, 90, 136, 162 Hyoscine, 89, 162 Hyoscyamus, 12. 61 Hyoscyamus albus, 154 Hyoscyamus aureus, 154 Hyoscyamus niger, 93, 145, 154 Hyoscyamus orientalis, 154 hyoscyamus piusillus, 154 Hypaphorine, 546
I
Idotetrandrine, 264, 294, 297, 309, 341 Incarvillea olgae, 471 Indicaine, 532 Indicaxanthine, 27 Indizoline, 517 Integerrimine, 520 Integerrisine, 543 Inula rogleana, 58 Zphigenia, 69 Ipomoca, 63
SUBJECT INDEX
563
Iridomyrmex, 52 Isobellendine, 85 Isochondodendrine, 297 Isocorydine, 526 Isocromadurine, 520 Isoeuonyminol, 23 1 Isoevonine, 218, 237 Isoevorine, 218, 237 Isofangchinoline, 309 Isogentialutine, 448 I soharningtonine, 532 Isolaureline, 535 Isoliensinine, 361 Isooncinotine, 538 Isoplatydesmine, 539 Isothebaine, 31 Isoremerine, 535 Isotenuipine, 275 Isothalicberine, 257 Isotrilobine, 253, 262, 271 Zxanthus niscosus, 475
J
Jabobine, 545 Jasminine, 462 Jasminum domatiigerum, 476 Jasminum fruticans, 486 Jasminum gracile, 476 Jasmium lineare, 476 Jasminum SPP, 446, 463 Jaborosa, 62 Jatrorrhiza paimata, 258 Julocroron, 48
K
Knightia deplanchei, 87, 153, 532 Kokusagine, 537, 549 Kokusaginine, 539 Kreisiginone, 532 Kreysigia, 69 Kreysigia multiflora, 532
Laurifonine, 518 Laurotetanine, 535 Latura, 61 Lepista caespitosa, 5 17 Lepistine, 517 Leptorhabdos parvijlora, 450, 535 Leptorhabine, 450, 535 Lespedeza, 43 Liensinine, 361 Limacine, 309 Limacusine, 267 Lindera bemzoiin, 535 Liparis, 71 Lirine, 535 Liriodenine, 65, 526, 535, 536, 548 Liriodendron tulipifera, 535 Littorica, 69 Littorine, 104, 139 Lobelia, 17 Lomatogonium rotatum, 475 Loline, 65 Lolium, 66 Lonicera, 53 Lophocerine, 26 Lophophora diffusa, 535 Lunaria, 65 Lupinine, 25, 44 Lupinus, 71 Lyadine, 539 Lyaline, 539 Lycopersicum esculentum, 142 Lysicamine, 535 Lysine, 14 Lycocfonine, 58 Lycopersicon, 60 Lycopodine, 20 Lycopodium, 20 Lyconne, 67 Lysicanine, 65 Lysichitum camtschatcense, 65 Lythrine, 531
L
Ladenbergia, 57 Lagerine, 534 Lagerstroemia indiea, 534 Lamprobine, 20, 44 Lapanine, 540, 549 Laurifine, 5 18 Laurifinine, 518 Laurifoline, 55 1
M
Maculine, 549 Magnocurine, 536 Magnoflorine, 41, 551 Magnolamine, 336 Magnoline, 334 Magnolia obovata, 536 Mahonia aquifolia, 297 Malaxis, 71
564
SUBJECT INDEX
Malkangunin, 221, 241 Malkanguniol, 222, 245 Malonetia. 60 Mandragora, 61 Mandragora autumnalis, 154 Mandragora oficinarum, 94, 154 Mappiene, 536 Mappia foctida, 55, 536 Matrine, 20 Maytansine, 2 19 Maytenus arbutifolia, 218, 536 Maytenus buchanii, 2 19 Maytenus chuchuhuasha, 219 Maytenus ovaius, 215, 218 Maytenus senegalense, 218 Maytenus serrata, 218 Maytine, 215, 218, 220, 225 Maytol, 227 Maytolidine, 218, 220, 227 Maytoline, 215, 218, 220, 225 Melicope barbigera, 539 Melicope perspicuinerva, 537 Melicopidine, 515 Melicopine, 518 A'-Membrenone, 544 Menisarine, 357 Menispermum canadense, 297 Menispermum dauricum, 267 Menyanthes trifoliata, 449, 458 Meperidine, 101, I50 Merendera, 69 Mescaline, 25, 549 Mesembrine, 26 Mesembryanthemum, 26 N-Methylisopelletierine, 16 N-Methylpyrrolidine, 16 N-Methyltyramine, 65 Methysticodendron, 6 I Mesodine, 531 Meteloidine, 89, 141 Metaphanine, 394, 396, 424 6-Methoxyteeleanthine, 548 3a-(p-Methoxyphenylacetoxy)-Tropan-6po 1, 91 3-Methoxytyramine, 549 0-Methylancistrocladine, 5 12 6P(2-Methylbutanoyloxy) tropan-3a-o I , 90 3(3-Methylcrotonyl)-cassaine, 526 0-Methyldauricine, 275 N-Methyl-3,4-dimethoxy-fi-methoxy-
phenethylamine, 5 19 N-Methyl-3,4-dimethoxyphenethylamine, 519 Methylhernandine, 394, 412 0-Methyllagerine, 534 0-Methylmieranthine, 276 4-Methyl-2,6-naphthyridine, 5 13 0-Methyloxyacanthine, 292 0-Methylpellotine, 535 N-Methylplatydesminium, 544 0-Methylptelefolium, 543 0-Methylthalicberine, 297, 348 N-Methyltyramine, 539 0-Methyltyrophorinidine, 540 Miersine, 394 Micranthine, 253 Monocrotaline, 519, 520 Monomethyltetrandinium, 307 Morphine, 32 Munitagine, 33 Multiflorine, 5 15 Multifloramine, 532 Murrayacinine, 537 Murray a Koenigii, 537 Muscarine, 22 Mycobacterium smetmatis, 300, 309 Mycobacterium tuberculosis, 300 Myrrhina, 538
N
Namedine, 67 Neferine, 361 Nelumbo, 57 Nemuarine, 276 Nemuaron vieillardii, 276 Neoeuonymine, 218, 239 Neoevonine, 218, 237 Neogomesia agavioides, 5 13 Neooneinotine, 538 Neothiobinupharidine sulfoxide, 197, 200 Neosophoramine, 546 Nicandra, 61 Nicojiana, 6, 12, 17, 61 Nicotiana tabacum, I54 Nicotine, 20, 25 Nigella damascena, 46 Nitidine, 551 Nohilomethylene, 524 4 Noractinidine, 446 Noradrenaline, 34
SUBJECT INDEX
565
Noratropine, 89 Norbelladine, 67 2-N-Norberbamine, 277 Norboldine, 543 Norcocaine, 123 Norcycleanine, 297 Norerythrostachaldine, 526 Norglaucine, 512 Norhyoscine, 89 Norlaudanosine, 30 Normacromerine, 519 N-Normethylskytanthine, 445 2-N-Norobamegine, 278 Norpseudoephedrine, 217 Norpsicaine, 134 Nortilliacorine-A, 278 , Nortiliacorinine-A, 278 Nortiliacorinine-B, 278 Novacaine, 164 Nuciferine, 65 Nudiflorine, 48 Nuphamine, 185, 188 Nuphar, 57, 72 Nupharamine, 183, 185, 211 Nupharidine, 181 Nuphar japonicum, 188 Nuphar luteum, 186, 197 Nupharolidine, 191, 199 Nupharolutine, 192, 199 Nuphenine, 187, 199 Nuphleine, 198, 200 Nymphaea, 57, 72 0 Obaderine, 260, 357 Obovanine, 536 Olea paniculaia, 462 Oliveridine, 463 Oliveramine, 465 Oncinotine, 538 Oncinoris nijida, 538 Ophelia diluta, 475 Opuntia clavata, 539 Opuntia jicus-indica, 27 Orientalinol, 34 Orientalinone, 31 Ormocastrine, 541 Ormosanine, 549 Ormosia, 23, 44 Ormosia semicastrata, 541 Ornithine, 14
Oscine, 143 Oxaline, 540 6,7-Oxidodeoxynupharidine,199 Oxodaphnigraciline, 521 Oxodaphnigracine, 521 16-Oxodelavaine, 394, 409 Oxoepistephanine, 279 16-Oxohasubanonine, 394, 405 16-Oxoprometaphanine, 394, 405 Oxostephamiersine, 394, 403 Oxyacanthine, 348
P
Pachygone pubescens, 297 Pachysandra, 60 Pakistanamine, 280 Pakistanine, 281 Palustrine, 20 Panamine, 549 Pandaca calcarea, 539 Pandaca debragi, 539 Pandine, 539 Pandoline, 539 Papaver, 6, 12, 38 Papaver orientale, 31 Papaver somniferum, 30 Papaverine, 30 Parthenium, 5 Passijlora coerulea, 539 Passiyora decaisneana, 539 Passijora edulis, 539 Passij7ora foetida, 539 Passijora incarnara, 539 Passijlora, subpeltata, 539 Passijlora subulata, 539 Passijlora warmingii, 539 Pauridianiha hyaflii, 539 Pauwoljia verticillata, 448 Pedicularidine, 467 Pedicularine, 467 'Pedicularis dolichorrhiza, 47 I Pedicularis ludwigi Regel, 471 Pedicularis olgae, 443, 466 Pedicularis rhinanthoides, 472 Pedicularis rhinanthoides, 438 Pediculidine, 461 Pediculine, 467 Pediculinine, 466 Peganum, 23, 42 Pelea barbigera, 539 Pelecyphora aselliformis, 5 13
566
Penduline, 282 Penicillium, 22 Penicillium islandicum, 6 Penicillium oxalicum, 540 Pennsylpavine, 306 Pennsylpavoline, 306 Pennsylvanamine, 306 Pennsylvanine, 306 Pergularia pallida, 540 Peripentadenia mearsii, 49, 92, 153 Periphylline, 540 Peripterygia marginata, 540 Petteria ramentacca, 540 Phaeanthine, 341 Phaeanthus ebracteolatus, 3 I0 Phaseolus aureus, 46 PPhenethylamine, 525, 543, 546 Phelline, 51 Phellodendron, 41 Phenethylamine, 14 Phenylalanine, 14, 43 2-Phenylglyceric Acid, 91 Phlebicine, 308 Phyllanthus, 47, 49 Physalis. 61 Physalis alkakengi, 94, 154 Physalis bunyardii, 94 Physalis peruviana, 94, 141, 154 Physochlaina, 61 Physochlaina alaica, 91, 154, 541 Physochlaine, 91, 541 Physostigma, 23, 49 Physosrigma vertenosum, 43 Physostigmine, 23 Physoperuvine, 94 Picrasma ailrnthoides, 42 Pilocarpine, 19 Pilocarpus, 19 Pilocarpus microphyllus, 541 Pilosine, 541 Pinidine, 20 Piper trichostachyon, 541 Piptanthine, 549 Pipranrhus, 44 Plantago albicans, 471 Plantago coronopus, 47 1 Plantago crassifolia, 47 I Plantago crypsoides, 47 1 Plantago cylindrica, 471, 443 Plantago major, 471 P!antago notata, 471
SUBJECT INDEX
Plantago ovata, 472 Plantago psyllium, 47 I Plantago ramosa, 443 Plantagonine, 443 Platydesmine, 537 Pleurospermine, 37 Podopetaline, 541 Podopetulum ormondii, 541 Popowia cyanocaupa, 275 Poranthera corymbosa, 542 Poranthericine, 542 Porantheridine, 542 Porantherilidine, 542 Parantheriline, 542 Porantherine, 542 Pretazettine, 67 Prometaphanine, 394 6PFropanoyloxy-3a-tigloyloxytropane, 90 Propyleine, 538 Prosopis nigra, 543 Prosopis spicigera, 543 Protostephabyssine, 394, 401 Protostephanine, 427 Przewalskia shebbearei, 154 Przewalskia tangiotica, 154 Pseudoephedrine, 15 Pseudotropine, 51, 109 Pseudornonas putida, 165 Psicaine, 107 Psilocybe, 22 Psilocybin, 18, 22 Psychotria, 57 Pielen trifoliata, 543 Pterocelastrus marginatus, 540 Pumiliotoxin C , 522 Putrescine, 16 Pycnamine, 283, 209 Pycnarrhena australiana, 277, 297 Pycnarrhena ozantha, 258, 278
R
Remijia, 57 Repandine, 357 Retama monosperma, 543 Retamine, 543 Reianilla ephedra , 5 43 (+)-Reticuline, 30, 520, 526, 536, 419 Retronecine, 545 Retrorsine, 545 Rhazya, 54
SUBJECT INDEX
567
Ricinine, 48 Ricinus, 48 Rivea, 63 Robustine, 551 Rodiasine, 274 Ruta bracteosa, 544 Ruta chalepensis, 544 Rutamine, 544 S
Salpichroa, 61 Salpichroa originifolia, 154 Salpiglossis, 61 Salsolidine, 525 Salsoline, 25 Salutaridine, 32 Sanguidimerine, 304 Sanguinaria canadensis, 304 Sarcocca, 60 Sceletenone, 544 Sceletium namaquense, 544 Sceletium strictum, 544 Schoenocaulon, 69 Scopolia, 61 Scopolamine, 162 Scopolia carniolica, 94, 154 Scopolia himalaiensis, 140, 154 Scopolia japanica, 155 Scopolia lurida, 94, 136, 145, 155 Scopolia parviyora, 155 Scopolia sinesis, 155 Scopalia stramonifolia, 145, 155 Scopolia tangutica, 155 Scopoline, 131 Securinega, 47 Securinine, 47 Sedamine, 17 Sedumo maximum, 545 Senecio barbellatus, 546 Senecio cineraria, 545 Senecio eraticus, 545 Senecio petasites, 545 Senecio swaziensis, 546 Senecionine, 19, 545 Seneciphylline, 545 Serotonin, 18 Sida cordifolia, 546 Silene, 10 Sinicuichine, 531 Skimmiancine, 531, 537, 544, 546, 549, 551 Skytanthine, 433
Skythanthines, 434, 470 GSkythanthine, 435 Skytanthus acutus, 432 Solandra, 61 Solandra grandijlora, 143, 155 Solandra guttata, 155 Solandra harrwegii, 155 Solandra hirsuta, 155 Solandra macrantha, I55 Solanidine, 60 Solanocapsine, 60 Solanurn, 60, 61 Sophocarpine, 543, 546 Sophora alopeouroides, 546 Sophora prodanii, 547 Sophoramine, 546 Sophoridine, 546 Sphaerocarpine, 45 Sparteine, 44, 20, 543. 547 Spathiostemon javensis, 49 Spherophysine, 547 Spicigerine, 543 Spiraea japonica, 58 Stehisimine, 297, 309 Stemmadinine, 54 Stephaboline, 394, 401 Stephamiersine, 394, 403 . Stephania abyssinica, 394 Stephania cepharantha, 261, 394 Stephania delavayi, 394 Stephania hernandifolia, 279, 297, 394 Stephania japonica, 283, 394 Stephania sasakii, 297, 394 Stepinonine, 283, 310, 347 Stephasunoline, 394, 403 Stephavanine, 394, 400 Stephisoferuline, 394, 398 Stephuline, 399 Streptomyces, 22 Streptomyces N337, 547 Streptosolen, 61 Stropharia, 22 Strychnine, 54 Strychnos, 54 Strychnos vacacoua, 450 Swainsonia coronillaefolia, 547 Swainsonia galegifolia, 547 Swazine, 546 Swentia connata, 475 Swentia gracipora, 475 Swertia gracij?ifolia, 476
568
Swertia japonica, 453, 456 Swertia marginata, 475 Swertia sibirica, 475 Syneilesis palrnata, 547 Syneilsine, 547 T
SUBJECT INDEX
Tabersonine, 54 Talauma mexicana, 381, 548 Taxine, 20 Tazettine, 67 Teclea boiviniana, 548 Teclea grandifolia, 548 Teclea unifoliata, 549 Teclea verdoerniana, 544 Tecleanone, 548 Tecleanthine, 548 Tecoma fulva, 440 Tecoma radicans, 440 Tecoma stuns, 435 Tecomaine, 435 Tecomine, 435 Tecostanine, 30, 435 Tecostidine, 437, 438 Telobine, 285 Teloidine, 11 1 Teloidinone, 111 Ternbetarine, 551 Templetonia retusa, 549 Templetine, 548 Tetrahydroharman, 25, 515 Tetrandrine, 266, 297, 309, 341 Thalfine, 286 Thalfinine, 287 Thalfoefidine, 255 Thalibruinine, 308 Thalicarpine, 289, 297, 382 Thalicberine, 297, 348 Thalictrogarnine, 287 Thalictropine, 288 Thalictrum dioicum, 289 Thalictrum foetidum, 286 ThalictrumJlavum, 297 Thalictrum glaucum, 292 Thalictrum isopyroides, 289 Thalictrum minus, 269, 290, 297 Thalictrum polygamum, 287, 297, 306 Thalictrum rochebrunianum, 308 Thalictrum rugosum, 292, 297 Thalidasine, 255, 293 Thalidazine, 297
Thalidoxine, 289 Thaligine, 294 Thalisopidine, 289 Thalmelatidine, 290 Thalmineline, 291 Thalrugosarnine, 292 Thalrugosidine, 293 Thalrugosine, 294, 309 Thalsrninine, 297 Thiobinupharidine, 195 Thionupharodioline, 200 Thionupharoline, 198, 200 Thionuphlutine, 196 Tigloyidine, 140 3a-Tigloyloxytropan-6p01, 89 6~-Tigloyjoxytropan-3a-7pdiol,89 Tiliacora dinklagei, 305 Tiliacora funifera, 274 Tiliacora racemosa, 278 Tiliacora warneckei, 274 Tiliacorine, 279, 359 Tiliacorinine, 279, 359 Tiliageine, 305 Toddalia, 41 Toxicoferine, 295 Trewia, 48 Trichocereus pachanoi, 549 Trichoderma viride, 22 Trichodesmine, 520 Triclisia gillettii, 262, 309 Triclisia patens, 309 Triclisia subcordata, 262, 296, 309 Tricordatine, 296 Tricrotonylteteamine, 546 Trigilletine, 262 Trilobine, 270, 297, 354 3a-(3,4,5-Trimethoxybenzogloxy)-tropane, 93 Triptergine, 240 Tripterygium forrestii, 246 Tripterygium wilfordii, 217, 218, 536 Tropacine, 164 Tropcocaine, 92, 162 Tropan-3a, 6P-dio1, 86, 91, 93 Tropan-2& 3P-dio1, 116 Tropane, 109, 123 Tropan-3a-01, 121 Tropan-3P-01, 101 Tropan-6po1, 123 Tropan-3-one, 12 1 Tropan-3a, 6P, 7ptrio1, 93
SUBJECT INDEX
569
Tropanyl Ethers, 124 Tropidine, 109, 133 Tropine, 61, 109 Tropinone, 109 Tryptarnine, 543 Tryptophane, 14, 43 Tubocurarine, 251, 255, 363 Tubocurine, 251, 296 Tuperostemonine,. 70 Tylophora, 56, 64 Tylophora asthmatica, 550 Tylophora cordifolia, 549 Tylophoraflava, 549 Tylophora indica, 550 Tylophorine, 37, 56, 64, 540, 549 Tylophorinidine, 540, 550 Tylophorinine, 549 Tyrarnine, 14, 65, 514, 525, 543 Tyrosine, 14, 43
Vasicinone, 546 Vavicinol, 546 Veatchine, 58 Venoterpine, 448 Veratrurn, 60, 69 Verbascum nobile, 466 Verbascum songaricum, 472 Vertalline, 537 Vincetoxicum, 56, 64
W
Wilfordic Acid, 217, 229 Wilfordine, 218, 240 Wilforgine, 218, 241 Wilforine, 218, 241 Wilfortrine, 241 Wilforzine, 218, 241 Withania, 62 Y Yohimbine, 49 Yuzurine, 521 Z Zanthoxylum, 41 Zanthoxylum americanum, 55 1 Zanthoxylum arnottianum, 55 1 Zanthoxylum clava-herculis, 55 1 Zanthoxylum tsihanimposa, 551 Zygadenus, 69
U
Uluganine, 550 Ulugbeckia tschirnganica, 550
V
Vacciniurn, 550 Valeriana oficinalis, 440, 442 Valeriana stolonifera, 486 Valeroidine, 92 Valtropine, 144 Vasicine, 549
A
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The Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167

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THE ALKALOIDS

Chemistry and Physiology

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A Subsidiary of Harcourt Brace Jovanovich, Publishers

COPYRIGHT 0 1977, BY ACADEMIC PRESS, INC.

ACADEMIC PRESS, INC.

111 Fifth Avenue. New York, New York 10003

United Kingdom Edition published b y ACADEMIC PRESS, INC. (LONDON) LTD.

PRINTED IN THE UNITED STATES OF AMERICA

LIST OF CONTRIBUTORS.. ....................................................

Chapter 1. Plant Systematics and Alkaloids S. SEIGLER DAVID

Chapter 2. The Tropane Alkaloids L. CLARKE ROBERT

I. Introduction ... 11. New Tropane A1

Chapter 3. Nuphar Alkaloids JERZY T. W R ~ B E L

Chapter 4. Celestraceae Alkaloids ROGER M. SMITH I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

393 395 395 414 419 427 428

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* Present address: Calle Peria 3166-9A, Buenos Aires, Argentina.

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CONTENTS OF PREVIOUS VOLUMES

1 15 91 107 165 271 375

Contents of Volume III

247 313 339 363

CONTENTS OF PREVIOUS VOLUMES

77 119 147 167 199 249 253 265 275

1 79 109 141 163 211 229 243 265 259 301

1 31 35 123 145 179 219 247 289

Contents of Volume VII

1 201 229 247 253 319 343 363

CONTENTS OF PREVIOUS VOLUMES

Contents of Volume VIII

1 27 47 55 59 93 119 159 203 238

CONTENTS OF PREVIOUS VOLUMES

CONTENTS OF PREVIOUS VOLUMES

Contents of Volume XI1

Contents of Volume XIII

CONTENTS OF PREVIOUS VOLUMES

PLANT SYSTEMATICS A N D ALKALOIDS

A. RELATIONSHIP OF CHEMICAL DATA TO BOTANICAL DATA

111. Application of the Data to Biological Problems

A. NATURE AND SOURCES OF VARIATION IN PLANTS

B. BASICPATHWAYS OF ALKALOID BIOSYNTHESIS

CHa CHa CHNH, COaH

CHa CH, CH,-NH,

IV. Alkaloids in Lower Vascular Plants and Gymnosperms

V. Alkaloids in the Angiosperms

B. THE MAGNOLIOPSIDA (DICOTYLEDONOUS PLANTS)

The subclass Caryophyllidae is recognized by Cronquist as having

Polygonales, Plumbaginales, and Batales are largely without alkaloids

1 . Subclasses of Magnoliopsida according to Cronquist (6).

Acronycine (an acridine alkaloid)

Skimmianine (a furoquinoline alkaloid)

Casimiroine (a quinoline alkaloid) CH,O

Arborine (a quinazoline alkaloid)

Hortiacine (an indoloquinazoline alkaloid)

R, = long, R, = short chain fatty acid

Hamemelidae Eucommiaceae Hamamelidaceae (Liquidambar)

Dilleniidae Ac tinidaceae Ericaceae Proteaceae

11. Alkaloids with Sesquiterpene Structures

13. Alkaloids Containing Steroidal or Triterpenoid Nuclei

SOLANACEAE THAT CONTAIN ALKALOIDS DERIVED FROM ORNITHINE AND LYSINE