Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist.

The neoclerodane diterpene salvinorin A (1) was isolated in 1982 from the rare mint SalVia diVinorum, indigenous to Oaxaca, Mexico.1 Recent efforts established salvinorin A as a potent and selective κ opioid receptor agonist, the only non-alkaloid psychoactive substance, and the most potent naturally occurring hallucinogen.2 As a result of its therapeutic potential, renewed isolation efforts have discovered a number of related salvinorin congeners,3 and a number of analogues of 1 have been prepared by semisynthesis to probe the pharmacophore and mode of binding.4 This communication describes the first synthesis of this natural product. Construction of the tricyclic salvinorin core is predicated on the proposed transannular5 Michael reaction cascade6 of bisenone macrocycle 3 (Scheme 1). Conformational analysis7 of 3 leads to a prediction wherein the resident stereocenters at C2, C4, and C12 should mutually reinforce the desired stereochemical course of the reaction. This plan permits the convergent assembly of vinyl iodide 4 and aldehyde 5, which can be prepared through established methods. The synthesis of aldehyde 5 began with the Ni(II)-(R)-BINAPcatalyzed orthoester alkylation8 of thiazolidinethione 6, followed by a subsequent Claisen condensation with ethyl hydrogen malonate9 to give â-ketoester 7 (Scheme 2). Selective formation of the (Z)-enol phosphate permitted an Fe-catalyzed cross-coupling with methylmagnesium chloride10 to furnish trisubstituted olefin 8. Reduction to the unsaturated aldehyde then allowed a selective aldol addition of acetate-derived chiral auxiliary 9.11,12 The derived allylic alcohol was protected as the tert-butyldimethylsilyl (TBS) ether 10. After revealing the terminal aldehyde, an (-)-N-methylephedrine-mediated zinc acetylide addition13 provided propargylic alcohol 11 in good diastereoselectivity. Alcohol protection as the BOM ether was uniquely effected using NaHMDS and BOMCl at low temperature under Barbier conditions.14 Semi-hydrogenation, dihydroxylation,15 and oxidative cleavage furnished fragment 5. The synthesis of vinyl iodide 4 employed an asymmetric reduction of ketone 12 using (R)-B-Me-oxazaborolidene as catalyst16 to afford alcohol 13 (Scheme 3). Alkyne isomerization17 of 13 to 14 preceded carboalumination18 and TES-silyl ether protection. In the coupling event, chelate-controlled addition of the Grignard reagent derived from 4 to aldehyde 5 afforded allylic alcohol 15 (Scheme 4). A series of protecting group manipulations provided seco-acid 16; subsequent macrolactonization using the Shiina procedure,19 desilylation, and oxidation afforded macrocycle 3. Treatment of â-ketolactone 3 with TBAF at -78 °C and warming to 5 °C induced the selective transannular reaction cascade to afford tricycle 2 as a single diastereomer. The reaction delivers two quaternary methyl stereocenters at C5 and C9 in a 1,3-diaxial alignment from the corresponding â,â-disubstituted enones, moieties known to possess poor reactivity toward conjugate addition. To complete the synthesis, we employed a deoxygenation sequence involving enol triflate formation,20 palladium-catalyzed triflate reduction,21 and subsequent conjugate reduction22 to yield 17, epimeric at C8. Protonation from the R-face by t-BuOH in situ appears to be under kinetic as well as thermodynamic control, as epimerization studies conducted on 1 (DBU, 110 °C in toluene) result in a mixture of C8-epimers biased toward 8-epi-salvinorin A 19.23 Deprotection of both the C2 and C4 acetals in 17 followed by oxidation and esterification gave 8-epi-salvinorin B (18). Epimerization using K2CO3 in oxygen-free methanol followed by acylation produced salvinorin A (1), spectroscopically identical to previous Scheme 1. Synthesis Plan for Salvinorin A (1)