CHEMISTRY LETTERS, ,pp. 2015-2018, 1990.

@ 1990 The Chemical Society of Japan

The Absolute Stereochemistry Salvinorins of Masato KOREEDA,* Lindsey BROWN, and LeanderJ. VALDES ill Departmentof Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, U.S.A.

The absolutestereostructures the hallucinogenicditerpenessalvinorin A of and B have beenunambiguouslydeterminedby the use of the non-empirical exciton chirality circular dichroism method on their 1a,2a-dioldibenzoatederivative.

Recentinvestigations1,2) the hallucinogenicMexican mint Salvia divinorum3) of haveresulted in the isolation of the pharmacologicallyactive diterpenesalvinorin (~vinorin) A (1) and its desacetylanalog salvinorin B (2). Extensive 1H and 13CNMR studieson thesetrans-clerodanes1,2) their derivatives,2)as and well as single-crystalX -ray analysis,1,2) have led to the formulation of the structuresof thesecompounds. The absolute stereochemistry the salvinorinswas postulatedbasedon the observednegative n ~ 1t*Cotton of effect of the I-ketone around 295 nm in their circular dichroism (CD) spectra.1,2) While this assignment had appeared be corroboratedby the negative n ~ 1t* Cotton effect of isofructicolone,4)the ambiguousnature to of the approachassociated with this empirical CD method necessitated independent,unequivocal an verification of the absolutestereochemistry. In the following, we delineatethe unambiguousassignment of the absolutestereochemistry thesephysiologically importantditerpenesthroughthe use of the non-empirical of exciton chirality CD method.5)

R1O"" 0

1 2 3

R1 = Ac, R2 = R3= 0 R1 = H, R2 = R3 = 0 R1 = R2 = H, R3 = OH

-COOCHa

In an effort to obtain a salvinorin derivative possessing a-diol systemwhich can be transformedinto an the dibenzoateesterrequired for the exciton chirality CD method, salvinorin A (1) or B (2) was treatedwith sodium borohydride in various protic solvents. The products having the la,2a-diol group were obtained in

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high yield. However, this reductionwas accompaniedby extensiveisomerization at C-8.. While mechanistic details for this unexpectedobservationremainto be establishedat this time, the isomerizationat C-8 appears to be the result of the base-promoted cleavageof the C-8/9 bond under the reactionconditions followed by the reclosureto provide the 8-epimerprior to the reduction of the 1ketone. Furthermore,attemptsto obtain the 1,2-dibenzoate derivative of the major reduction product3 undervarious benzoylatingconditions invariably produced only the 2-monobenzoate. Since it was deemeddesirableto removepossible interactionbetweenthe benzoate and the furan chromophoresfor the unambiguousCD analysis, salvinorin A (1) was reduced undercatalytic hydrogenation conditions, providing the hexahydroderivative 4 (a 2:1 epimeric mixture at C-13) after esterification with diazomethane and desacetylationwith KCN/MeOH.6) Interestingly, ester4 was found to be relatively stable towards configurational isomerization at C-8. Thus, reduction of 4 with NaBlI4 in EtOH produced cleanly the cis-la,2a-dioI5 in 81% yield. The benzoylation of the la-hydr:cyl group in 5, which is surroundedby the two 1,3-diaxiallyjuxtaposed methyl groups,proved to be quite difficult underthe standardbenzoylation conditions. However, treatmentof 5 with trimethyl orthobenzoate 100 C in the presenceof a catalytic at amountof benzoic acid followed by acid-catalysed hydrolysis of the resulting 1,2-cyclic orthobenzoate provided the I-monobenzoatederivative of 5.7,8) Benzoylation of this monobenzoate under standardconditions afforded the desired 1,2-dibenzoate in 95% yield. Alternatively, treatmentof diol5 69) with benzoyl trifluoromethanesulfonate(BzOTf)10)resulted in the direct formation of 6 in 50% yield.

0 !",!~"".//,~,

CH300C!~--~~OI
CHa

~Y

'\;11
0

f
0

(:)
Fig. 1. The negative chirality betweenthe two benzoate electric transition dipoles of the 1,2-dibenzoate derivative 6.

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i, ii, and iii

HO ""

"COOCHa

COOCHa

IV

BzO BzO '" "COOCHa'

HO

=
~

d " v, VI, an VII or viii

HO

'"
=
~

"COOCHa

=
-6

:
5

COOCHa

COOCHa

Scheme1. Reagentsand conditions: i, H2, 5% Pd/C/MeOH, 14h; ii, CH2N2fMeOH, 0 C, 2 h; iii, KCN (3.0 equiv.)/MeOH, reflux, 15 min [74% yield for 1 ~ 4]; iv, NaBlI4 (5.0 molarequiv.)/abs. EtOH, 0 C ~ room temperature,12 h (81%); v, PhC(OMe)3(excess),PhCOOH (catalytic), 100 C, 1 h; vi, rnF/water/AcOH (15/5/1), conc. HCl (2 drops) (65% yield for V and vi); vii, BzCl (excess)/pyridine,room temperature,2 h (95%); viii, BzOTf(5.0 equiv.), pyridine (7.5 equiv.)/CH2Ci2, -78 C ~ room temperature, 1 h at room temperature(50%). The CD spectrumof the 1,2-dibenzoat~ in 9:1 MeOH/dioxaneshoweda pair of typical exciton-split 6 Cotton effects with oppositesignscentredupon the UV absorption(227 nm) of the benzoatechromophore: &235.5 -15.9 and LlE221.5 +6.66. The negative longer wavelengthCotton effect clearly defines the negative chirality betweenthe two electric transitiondipoles of the benzoate chromophores assignable the long axis 7t to ~ 7t*transitions (Fig. 1),5)thus unequivocally assigningthe absolutestereostructures salvinorin A and B of as given in 1 and 2, respectively.

The National Institutes of Health (CA 25185)are gratefully acknowledgedfor fmancial supportof this

work.

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References 1) A. Ortega, F. Blount, andP. S. Manchand, Chern. J. J. Soc.,Perkin Trans 1, 1982,2505. 2) L. J. Valdesill, W. M. Butler, G. M. Hatfield,A. G. Paul,andM. Koreeda, Org. Chern., J. 49, 4716(1984). 3) L. J. Valdesill, J. L. Diaz, andA. G. Paul,J. Ethnopharmacol., 287(1983);L. J. Valdesill, G. 7, M. Hatfield, M. Koreeda, A. G. Paul,Econorn.Botany,41,283 (1987). and 4) M. Martinez-Ripoll, Fayos,B. Rodriguez, C. Garcia-Alvarez, Savona, Piozzi,M. J. M. G. F. Paternostro, J. R. Hanson, Chern.Soc.,Perkin Trans.1, 1981,1186. and J. 5) N. Harada K. Nakanishi, and "CircularDichroicSpectroscopy -Exciton Couplingin Organic Stereochemistry," Univ. Sci.Books,Mill Valley, California,1983. 6) K. Mori, M. Tominaga, Takagawa, M. Mitsui, Synthesis, T. and 1973,790. 7) J. F. King andA. D. Allbutt, Can.J. Chern., 1754(1970);M. Koreeda, N. Akhtar, D. R. 48, M. Boyd,J. D. Neill, D. T. Gibson,andD. M. Jerina, Org. Chern., 1023(1978);L. J. Valdesill J. 43, andM. Koreeda, Ibid., in press. 8) Fordiscussions the mechanism thisreaction, P. Deslongchamps, on of see: "StericEffectsin Organic Chemistry,"Pergamon Press, Oxford (1983),pp. 82-85. 9) IH NMR (500 MHz, CDCI3)~ 1.121(s,3H), 1.544(s, 3H), 2.08 -2.23 (m, 2H), 2.41 -2.56 (m, 3H), 3.419(dd, IH, J = 7.6,7.6 Hz), 3.445*(dd, 1H,J = 8.4, 8.4Hz), 3.647(s, 3H), 3.715(s, 3H), 3.75 -4.03 (m, 3H), 5.051 (ddd, IH, J = 11.8,4.5,3.5 Hz), 6.024*(m, IH), 6.047(m, 1H; the observed 1/2 3.8 Hz uponirradiationof the5.051ppmpeak),7.259(dd, 2H, J = 8.0,7.6 Hz), W = 7.457(tt, 1H, J = 7.6,1.2 Hz), 7.494(dd, 2H, J = 8.1, 7.7Hz), 7.620(tt, 1H,J = 7.7,1.4 Hz), 7.756(dd, 2H,J= 8.0, 1.2Hz), and8.043 ppm(dd,2H,J=8.1, 1.4Hz). The peakswith asterisks indicate thoseof the spectroscopically resolved minorC-13epimer. 10) M. KoreedaandL. Brown,J. Chern. Soc.,Chern.Cornrnun., 1983, 1113;L. Brown andM. Koreeda, J. Org. Chern., 3875(1984). 49,

(Received August 6,1990)