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CHEMISTRY LETTERS, pp. 2015-2018, 1990. @ 1990 The Chemical Society of Japan,

The Absolute Stereochemistry f SalvinorinsMasato KOREEDA,* Lindsey BROWN, and LeanderJ. VALDES ill

Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, U.S.A.

The absolutestereostructures f the hallucinogenicditerpenessalvinorin Aand B have beenunambiguouslydeterminedby the use of the non-empiricalexciton chirality circular dichroism method on their 1a,2a-dioldibenzoatederivative.

Recent nvestigations1,2) f the hallucinogenicMexican mint Salvia divinorum3) ave resulted n theisolation of the pharmacologicallyactive diterpene salvinorin (~vinorin) A (1) and ts desacetylanalogsalvinorin B (2). Extensive 1H and 13CNMR studieson these rans-clerodanes1,2)nd their derivatives,2)aswell as single-crystal X -ray analysis,1,2) ave ed to the formulation of the structuresof thesecompounds.The absolute stereochemistry f the salvinorins was postulatedbasedon the observednegative n ~ 1t*Cottoneffect of the I-ketone around 295 nm in their circular dichroism (CD) spectra.1,2)While this assignment adappeared o be corroboratedby the negative n ~ 1t* Cotton effect of isofructicolone,4) he ambiguousnatureof the approachassociatedwith this empirical CD method necessitated n ndependent,unequivocalverification of the absolutestereochemistry. n the following, we delineate he unambiguousassignment fthe absolute stereochemistry f thesephysiologically importantditerpenes hrough he use of the non-empiricalexciton chirality CD method.5)

R1O"" 1 R1 = Ac, R2 = R3= 00 2 R1 = H, R2 = R3 = 03 R1 = R2 = H, R3 = OH--

COOCHaIn an effort to obtain a salvinorin derivative possessing n a-diol systemwhich can be transformed nto

the dibenzoateester equired for the exciton chirality CD method, salvinorin A (1) or B (2) was treated withsodium borohydride in various protic solvents. The products having the la,2a-diol group were obtained n

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2016 Chemistry Letters, 1 990high yield. However, this reduction was accompaniedby extensive somerization at C-8.. While mechanisticdetails for this unexpectedobservation emain o be establishedat this time, the isomerizationat C-8 appears obe he result of the base-promoted leavageof the C-8/9 bond under he reaction conditions ollowed by thereclosure o provide the 8-epimer prior to the reduction of the 1- etone. Furthermore,attempts o obtain he1,2-dibenzoate erivative of the major reduction product 3 undervarious benzoylatingconditions invariablyproduced only the 2-monobenzoate.

Since t was deemeddesirable o removepossible nteractionbetween he benzoateand the furanchromophores or the unambiguousCD analysis, salvinorin A (1) was reduced undercatalytic hydrogenationconditions, providing the hexahydroderivative 4 (a 2:1 epimeric mixture at C-13) after esterification withdiazomethane nd desacetylationwith KCN/MeOH.6) Interestingly, ester4 was found to be relatively stabletowards configurational isomerization at C-8. Thus, reduction of 4 with NaBlI4 in EtOH produced cleanlythe cis-la,2a-dioI5 in 81 % yield. The benzoylation of the la-hydr:cyl group in 5, which is surroundedbythe two 1,3-diaxially uxtaposed methyl groups,proved to be quite difficult under he standardbenzoylationconditions. However, treatmentof 5 with trimethyl orthobenzoate t 100 C in the presenceof a catalyticamountof benzoic acid followed by acid-catalysed ydrolysis of the resulting 1,2-cyclic orthobenzoateprovided the I-monobenzoatederivative of 5.7,8) Benzoylation of this monobenzoateunderstandard onditions afforded the desired 1,2-dibenzoate 9) n 95% yield. Alternatively, treatmentof diol5with benzoyl trifluoromethanesulfonate BzOTf)10) esulted n the direct formation of 6 in 50% yield.

04 2 !",!~"".//,~,

CH300C!~--~~OI ~Y '\;11 fCHa 0 0

(:)Fig. 1. The negative chirality between he two benzoate lectric transitiondipoles of the 1,2-dibenzoate erivative 6.

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Chemistry Letters, 1 9 9 0 2017

HO "COOCHai, ii, and iii ""1 .COOCHa 4

IV

BzO HOBzO "COOCHa' d " HO "COOCHa'" v, VI, an VII '"-

or viii= = = :~ -6 ~ 5COOCHa COOCHa

Scheme 1. Reagentsand conditions: i, H2, 5% Pd/C/MeOH, 14 h; ii, CH2N2fMeOH, 0 C, 2 h; iii, KCN (3.0equiv.)/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, oomtemperature,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/dioxane showeda pair of typical exciton-splitCotton effects with opposite signs centredupon the UV absorption 227 nm) of the benzoatechromophore:&235.5 -15.9 and LlE221.56.66. The negative onger wavelengthCotton effect clearly defines the negativechirality between he two electric transitiondipoles of the benzoate hromophores ssignable o the long axis 7t~ 7t* ransitions (Fig. 1),5) hus unequivocally assigning he absolutestereostructures f salvinorin A and Bas given in 1 and 2, respectively.

The National Institutes of Health (CA 25185)are gratefully acknowledged or fmancial supportof thiswork.

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2018 -) Chemistry etters, 1 99 0References

1) A. Ortega, . F. Blount, andP. S. Manchand, . Chern.Soc.,Perkin Trans 1, 1982,2505.2) L. J. Valdes ll, W. M. Butler, G. M. Hatfield,A. G. Paul,andM. Koreeda, . Org. Chern., 9,

4716 (1984).3) L. J. Valdes ll, J. L. Diaz, andA. G. Paul,J. Ethnopharmacol.,, 287 1983);L. J. Valdes ll, G.M. Hatfield, M. Koreeda, ndA. G. Paul,Econorn.Botany,41,283 (1987).4) M. Martinez-Ripoll, . Fayos,B. Rodriguez,M. C. Garcia-Alvarez, . Savona, . Piozzi,M.

Paternostro, nd J. R. Hanson, . Chern.Soc.,Perkin Trans. 1, 1981,1186.5) N. Harada ndK. Nakanishi, CircularDichroic SpectroscopyExciton Coupling n Organic

Stereochemistry,"niv. Sci. Books,Mill Valley, California,1983.6) K. Mori, M. Tominaga,T. Takagawa, nd M. Mitsui, Synthesis,973,790.7) J. F. King andA. D. Allbutt, Can.J. Chern., 8, 1754 1970);M. Koreeda,M. N. Akhtar, D. R.

Boyd,J. D. Neill, D. T. Gibson,andD. M. Jerina, . Org. Chern., 3, 1023 1978);L. J. Valdes llandM. Koreeda, bid., in press.8) Fordiscussions n he mechanismf this eaction, ee:P. Deslongchamps,StericEffects n OrganicChemistry,"Pergamon ress,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; theobservedW 1/2= 3.8 Hz upon rradiationof the5.051ppmpeak),7.259 dd, 2H, J = 8.0,7.6 Hz),7.457(tt, 1H, J = 7.6,1.2 Hz), 7.494 dd, 2H, J = 8.1, 7.7 Hz), 7.620 tt, 1H,J = 7.7,1.4 Hz),7.756 dd, 2H,J= 8.0, 1.2Hz), and 8.043 ppm(dd,2H,J=8.1, 1.4Hz). The peakswith asterisksindicate hoseof the spectroscopicallyesolvedminorC-13epimer.

10) M. KoreedaandL. Brown, J. Chern.Soc.,Chern.Cornrnun., 983, 1113;L. Brown and M. Koreeda,J. Org. Chern., 9, 3875 1984).

(Received ugust 6,1990)