Synthesis of Morphine Alkaloids

MeO CO2H HO NH2 MeO OH HO NMe MeN OH O OH

D N B A

C OH O E

Introduction

Cultivation:
Opium is harvested from the immature poppy seed capsule

OH O OH MeN (-)-morphine 10 -15 % MeN

OMe O OH

MeO

O H N

Me

(-)-codeine 3-4%

MeO (-)-thebaine 1-2 %

Fig 1: Lanced Poppy with raw opium exturding

Primary areas of cultivation are south east and west asia and latin america An average Indian acreage of P. somniferum yields 25-30 kg of opium

Introduction

History of Morphine as a Pharmaceutical

Laudanum (16th Century): -Developed by Swiss alchemist Paracelus -alcoholic tincture of alcohol, opium, and other herbs -Eased suffering from the plague Heroin (1898): -Developed by Heinrich Dreser at Fredich Bayer and Company -Diacetyl derivative of morphine -Marketed to the German people as a cough remedy Morphine (Present day) -One of the most widely used drugs for treatment of severe pain

Introduction

Structure
D N B A Morphine C OH O E O H HO
6 7

HO
3 4

2 1 11 12 5 13 14 8 15 10 16 9

N Me

Key Features: 5 rings, 5 contiguous stereocenters, compact array of functionality

Synthesis
Landmark synthesis was in 1952 by Gates Since then at least 18 more total and formal synthesis of Morphine have appeared This overview will encompass 6 unique routes

Biosynthesis of Morphine
HO CO2H HO NH2 L-Tyrosine HO CHO HO (S)-norcoclaurine MeO (S)-reticuline HO NH2 dopamine HO HO NH H MeO HO HO NMe H

MeO HO NMe MeO OH salutaridinol SN2' MeO

MeO O NMe MeO O salutaridine

MeO O NMe MeO O Phenolic coupling

MeO HO NMe MeO OH (R)-reticuline

MeO

MeO

HO

O H MeO thebaine NMe

O H O neopinone NMe

O H O codeinone NMe H

O H HO morphine NMe H

Gates Synthesis

Retrosynthesis
MeO [Ox] O H HO Morphine [Red] N [Red] H O MeO HO N O Epimerization MeO HO
14

MeO MeO NC O O [4 + 2]

MeO MeO CN O OH Reductive Amidation

MeO MeO H O O NH

Gates Synthesis

Forward Synthesis: Diene

HO OH 1. BzCl 2. NaNO2 3. Pd/C 4. FeCl3 (56 %) BzO 5. SO2 O O 6. (MeO)2SO2 (78 %) OMe 7. KOH 8. NaNO2 9. Pd/C 10. FeCl3 (69 %) O O OMe NC OMe 1. NC CO2Et O OMe OMe O BzO OMe

NEt3 2. K3FeCN6 3. KOH,EtOH (82 %)

Gates Synthesis

Forward Synthesis: Morphine

MeO MeO O O CN AcOH/! (50 %) MeO MeO CN O OH 27 atm H2 CuO/Cr2O EtOH 150 C (50 %) MeO MeO H O 1. N2H4/KOH 2. MeI/NaH 3. LAH (76 %) MeO HO
14

O NH

1. (a) Br2 (b) 2,4-DNP H N 2. HCl 3. H2/ PtO2 (7 %)

MeO 1. H2SO4 HO
14

MeO

2. KOH, MeO (HOCH2CH2)2O 3. KOt-Bu/Ph2CO (14 %)

Gates Synthesis

Forward Synthesis: Morphine

MeO HO H O N 1. (a) Br2 (b) 2,4-DNP 2. HCl (8 %) MeO Br 1. LAH (44 %) O H O 1-Bromo-Codeinone N 2. Pyr-HCl, 220 C (34%) O H HO Morphine N MeO

Analysis: Gates Method

29 Steps Overall Yield: 0.0014%

MeO

O N H HO

Key Disconnections: Diels-Alder & Reductive Amidation

Rice Synthesis

Retrosynthesis
HO MeO MeO HO N O O NCHO Br

O N HO

CO2H

H2N

MeO HO

MeO H NH HO

Br

OH OMe OMe MeO

H NCHO

Rice Synthesis

Forward Synthesis: Grewe cyclization

CHO CO2H 1. a) NaHSO3 b) KCN, H2SO4 OH OMe 2. SnCl2, HCl HOAc (67 %) OH OMe 1. NH2 200 C 2. a) POCl3 b) NaCNBH4 (86 %) OMe MeO HO

H NH

MeO 1. Li/NH3 2. PhOCHO, EtOAc (85 %) MeO

MeO HO

Br NH4F/HF NCHO TfOH (60 %)

MeO HO

Br 1. a) MeSO3H b) (CH2OH)2 c) NBS d) HCO2H(aq) (90 %)

H NCHO

HO

H NH

MeO

Rice Synthesis

Forward Synthesis: End Game

MeO HO NCHO O Br 1. Br2, AcOH 2. CHCl3, NaOH 3. H2, Pd(C), CH2O, NaOAc (79 %) MeO 1. ClCO2Et 2. PhSeCl 3. NaIO4 N O Dihydrocodeinone 4. NaBH4 5. BBr3, CHCl3 (42 %) HO

O N HO Morphine

Analysis: Rice Method

16 steps Overall yield 12 % Grewe cyclization was key disconnection

HO

O N HO

Practical method for conversion of dihydrocodeinone to morphine

Evans Synthesis

Retrosynthesis
OH O HO O H2C H H N Me N H OMe MeO MeO OMe

Me Gates Intermediate

Me

- [CH2] OMe OMe OMe Br Br Br OMe N Me OMe OMe N H Me ClO4

N Me

Evans Synthesis

Forward Synthesis: Immonium Perchlorate

OMe O 1. N Me OMe Li N Me OMe OMe OMe 1. n-BuLi 2. Br Br OMe N OMe OMe N

2. TsOH, 110 C (43 %)

Me

Br

Me

3. NaI OMe OMe N H Me ClO4 MeOH 50 C 60 % overall, 95:5 cis:trans H Kinetic Product OMe HClO4 OMe N

OMe OMe N ClO4

Me

Me

Thermodynamic Product

Evans Synthesis

Forward Synthesis:
OMe OMe N H Me ClO4 CH2N2 DCM (95 %) H OMe OMe N Me H DMSO (95 %) OMe

OMe N Me CHO BF3-Et2O

Stereochemical Analysis: H Me N Ar Nu

MeN Nu H

H Ar MeO OMe

OH N Me

Evans Synthesis

Forward Synthesis:
OMe OMe N H Me ClO4 CH2N2 DCM (95 %) H OMe OMe N Me H DMSO (95 %) N Me CHO BF3-Et2O MeN Nu H H Ar MeO OMe OMe OMe

Stereochemical Analysis: H Me N Ar Nu

OH N Me

Evans Synthesis

Forward Synthesis: End Game

OMe MeO 1. MsCl, TEA OH N Me 2. LiEt3BH 3. OsO4, NaIO4 (80 %) O MeO O HO H OMe

OMe

Me Gates Intermediate

Me

Analysis: Evans Synthesis

Short sequence to achieve the gates intermediate (10 steps) Cleaver and original disconnect Major limitation is having to go through gates intermediate

Overman Synthesis

Retrosynthesis
OH O OH MeN (-)-morphine Heck Cyclization OHC I HN SiMe2Ph DBS OMe OBn Mannich DBS N I OBn OMe Rice O MeN O DBS N OMe Epoxide Opening OMe OBn

Overman Synthesis

Forward Synthesis: amine component

H 2. Ph Ph OCONHPh O O 5. n-BuLi, CuI(Ph3P)2 PhMe2SiLi (81 %) O SiMe2Ph 6. a) TsOH, NaIO4 Stereochemical Analysis: R2 Syn Facial O Oxidative Addition Cu N O R1 Ph H R1 Cu (III) N Ph R2 Reductive Elimination H R1 HN SiMe2Ph DBS b) DBS-NH2, NaCNBH3 (83 %)

OCH3 1.a) NH3 (l) CO2H b.) Li wire Cl c.) d.) HCl aq (27 %)

O, N B H catechol borane 3.
PhN C P

4. OsO4/NMO, Acetone (90 % ee, 68 %)

R2

DBS =

Overman Synthesis

Forward Synthesis: amine component

H 2. Ph Ph OCONHPh O O 5. n-BuLi, CuI(Ph3P)2 PhMe2SiLi (81 %) O SiMe2Ph 6. a) TsOH, NaIO4 Stereochemical Analysis: R2 Syn Facial O Oxidative Addition Cu N O R1 Ph H R1 Cu (III) N Ph R2 Reductive Elimination H R1 HN SiMe2Ph DBS b) DBS-NH2, NaCNBH3 (83 %)

OCH3 1.a) NH3 (l) CO2H b.) Li wire Cl c.) d.) HCl aq (27 %)

O, N B H catechol borane 3.
PhN C P

4. OsO4/NMO, Acetone (90 % ee, 68 %)

R2

DBS =

Overman Synthesis

Forward Synthesis: aldehyde component

CHO 1. HC(OMe)3, H MeO OMe CHO I BnO OMe 1. CH2SMe2 2. BF3 -THF (84 %) I BnO OMe CHO

n-BuLi; I2; HCl

MOMO OMe BnBr, K2CO3 (78 %)

HO OMe

2. NaH, ClCH2OMe (96 %)

Forward Synthesis: mannich reaction

OHC HN SiMe2Ph OMe Stereochemical Analysis: R1 Me3Si N H Vs. Me3Si N R2 H R1 I DBS OBn ZnI2 EtOH 60 C PhMe2Si N DBS H Ar 80 % dr > 20:1 DBS N I OBn OMe

R2 Favored for large R1

Favored for small R1

Overman Synthesis

Forward Synthesis: Heck Cyclization and End Game

OMe OMe 1. BF3-OEt 2. ArCO3H, CSA (60 %) DBS N HO 1. TPAP/NMO 2. H2, Pd/C, CH2O (69 %) OH O OH MeN (-)-morphine 1. ClCO2Et 2. PhSeCl 3. NaIO4 4. LAH 5. BBr3 (36 %) MeN OMe O O

DBS

N I OBn OMe (1)

Pd(TFA)2(PPh3)2 PMP, 120 C (60 %) DBS N OBn

Overman Synthesis

Forward Synthesis: Bis-Heck Cyclizations

O MeO2C N I OTBDMS OMe OMe OH O MeO2CN MeO2CN PdLn 1. H2C PPh3 2. TBAF, THF (47 %) MeO2C N I OH OMe

1. a) CH2O, ! b) ClCO2Me 2. a) EtSH, BF3 b) TMDSOTf 3. CrO3, 3-5-dimethyl pyrazole

OMe OsO4 O MeO2C O NaIO4 (70 %)

OMe

Pd(TFA)2(PPh3)2 PMP, 120 C (58 %)

Overman Synthesis

Analysis: Overman Approach

1st enantioselective synthesis that did not contain a resolution Natural and unnatural morphine available 23 steps with an overall yield of 0.56 % (single heck) 26 steps with an overall yield of 0.184 % (bis-cyclization) Key disconnections were the Heck and Mannich

OH O OH MeN

White Synthesis

Retrosynthesis
MeO Rice O O H NMe H O H O NMe Beckman O H MOMO H O MeO C-H Insertion O H MOMO H N2 H O MeO

MeO

H HO

MeO HO HO2C

MeO SEAr HO CO2Me 1. Stobbe 2. Hydrogenation O O CO2H

MeO Robinson HO O H O OH

MeO HO CHO MeO MeO

White Synthesis

Forward Synthesis:
MeO 1. (CH2CO2Me)2 CHO 2. H2, [RhCl(COD)]2, (-)-MOD-DIOP HO HO2C CO2Me 1. P2O5, MeOH 2. H2, Pd(OH)2 3. LiOH(aq), THF HO O CO2H 1. KH, HCO2Me 2. MVK, NEt3 3. NaOH, THF MeO

MeO HO

MeO O

Br

MeO HO Br O

Br DBU O OMe 70 C (80 %)

MeO HO Br H O

Br 1. CH2N2 O OMe

MeO HO O H O OH

O OMe

2. Br2, NaHCO3

White Synthesis

Forward Synthesis:
MeO O Br 1. NaBH4 O OMe 2. H2, Pd/C (77 %) MeO O H HO 22:1 H H 1. CH2(OMe)2 2. LiOH 3.( COCl)2 4. CH2N2 (50 %) MeO O H MOMO H N2 Rh2(OAc)4 (50 %) H

O OMe

MeO O H MOMO 11 H O NH

MeO O H MOMO 1 H N H O

MeO O H MOMO H AcO OBs NH 1. NH2OH-HCl

MeO O 2. p-BrPhSO2Cl, NaOAc H (63 %) MOMO

H O

White Synthesis

End Game:
MeO O H MOMO H O NH 1. NaH/MeI 2. HBr, MeCN 3. D-Mperiodinane (90 %) MeO O H O H O NMe 1. PhSeCl/MsOH 2. NaIO4 3. LiAlH4 4. BBr3 (52 %) MeO O H HO H NMe

Analysis: White Approach

29 steps Overall yield of 1.73 %

MeO O H HO H NMe

Asymmetry was introduced early via enantioselective hydrogenation Key disconnect was the Rhodium (II) catalyzed C-H insertion

Parker Synthesis

Retrosynthesis:
MeO Rice N morphine Me O H O N Me [Ox] O H HO N Me O H HO Radical Cyclization MeO OMe HO PhS Br OH TBDMSO NTs Me Mitusunobo Me N S R Ts MeO MeO Me N Ts

HO

O H HO

O H HO

Parker Synthesis

Forward Synthesis:
Racemic Route:
NH2 1. Li, NH3 2. a) TsCl, TEA b) 1N HCl 3. MeI, K2CO3 (75 %) NTs Me O (1) 1. NaBH4, CeCl3 2. MCPBA 3. Ti(Oi-Pr)4 4. TBDMSCl (63 %) HO TBDMSO racemic NTs Me

MeO

Asymmetric Route:
1. Br2, TEA 2. catechol borane (76 %, 80 % ee) Br HO NTs Me Na(Hg) (90 %) HO NTs Me 1. MCPBA 2. Ti(Oi-Pr)4 3. TBDMSCl (52 %) NTs Me

HO TBDMSO

enantiomerically enriched

Failed routes included direct CBS reduction of 1 (35 % ee) and Sharpless kinetic resolution of the allylic alcohol (44 %ee)

H (S)-B-Me =

Ph Ph

O N B Me

Parker Synthesis

Forward Synthesis: Mitsunobu Coupling

MeO HO Br CHO PhS MeO HO Br SPh

O P

n-BuLi
(OEt)2 THF (82 %)

MeO OMe HO PhS Br OH TBDMSO NTs Me 1. PBu3, DEAD 2. 10 % HF

O H HO

Br SPh

Me N Ts

Parker Synthesis

Forward Synthesis: Radical Cyclization

MeO Bu3SnH AIBN MeO Me N Ts (35 %) -[ SPh] MeO MeO Bond O H HO SPh Me N Ts Ts N Me Rotation O HO H OH O

O H HO

Br SPh

Me N Ts

O H HO

Ts N Me (11 %)

SPh Ts N Me

Parker Synthesis

Forward Synthesis: Radical Cyclization

MeO Bu3SnH AIBN MeO Me N Ts (35 %) -[ SPh] MeO MeO Bond O Draw a mechanism that accounts HO H Me SPh N Rotation for formation of the side product SPh Ts Ts N Me OH O

O H HO

Br SPh

Me N Ts

O H HO

Ts N Me (11 %)

O H HO

Ts N Me

Parker Synthesis

Forward Synthesis: Radical Cyclization

MeO Bu3SnH AIBN MeO Me N Ts (35 %) -[ SPh] MeO MeO Bond O H HO SPh Me N Ts Ts N Me Rotation O HO H OH O

O H HO

Br SPh

Me N Ts

O H HO

Ts N Me (11 %)

SPh Ts N Me

Parker Synthesis

End Game
MeO Me Li/NH3 N t -BuOH Ts (85 %) Me N MeO DMSO (COCl)2 (83 %) MeO

MeO

O H HO

O H HO

O H HO HO N

Me

O H N

Me

O dihydrocodeinone Rice Method O H HO morphine N Me

Parker Synthesis

Analysis: Parker Method

MeO

(+/-) Morphine: 22 steps Overall yield of 2.07 % Radical cyclization was the key disconnect First published in August, 1992 (-) Morphine: 24 steps Overall yield of 1.7 % CBS reduction of -bromoenone was key step Published in January, 2006
Br HO NTs Me

O H HO morphine N

Me

Conclusions

Disconnection approaches have evolved with the methods of synthetic chemisty

D N B A Morphine C OH O E Gates (1952): Diels-Alder Rice (1980): Grewe Cyclization Evans (1982): Iminium Salts Overman (1993): Heck chemistry White (1997): C-H insertion Parker (2006): Radical Cyclization Racemic Asymmetric

Morphine appoaches will contiune to grow

(Only Rice has come close to synthetically viable route)

with

Continued need for developing morphine derivaties which can attenuate addictive properties

References
Review:
Taber, D.F. The Enantioselective Synthesis of Morphine: Strategies and Tactics in Organic Synthesis 2004, 5, 353

Lead References for Syntheses:

Gates, M.J. J. Am. Chem. Soc. 1953, 75, 4340 Rice, C.; Brossi, A. J. Org. Chem. 1980, 45, 592 Evans, D.A.; Mitch, C.H. Tetrahedron Lett. 1982, 23, 285 Overman, L.E. Pure and Appl. Chem. 1994, 66, 1423 White, J.D. J. Org. Chem. 1999, 64, 7871 Parker, K.A. J. Org. Chem. 2006, 71, 449