Asymmetric synthesis of salvinorin A, a potent κ opioid receptor agonist

Article abstract of DOI:10.1021/ja073590a

The stereoselective synthesis of salvinorin A is described. A macrocyclic bis-Michael reaction cascade provides the requisite tricyclic skeleton as a single diastereomer. Copyright

Full text of DOI:10.1021/ja073590a

Published on Web 06/30/2007
Asymmetric Synthesis of Salvinorin A, A Potent K Opioid Receptor Agonist
Jonathan R. Scheerer, Jonathan F. Lawrence, Grace C. Wang, and David A. Evans*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received May 18, 2007; E-mail: evans@chemistry.harvard.edu
Scheme 1. Synthesis Plan for Salvinorin A (1)
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 psycho-
active substance, and the most potent naturally occurring hal-
lucinogen.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 semi-
synthesis 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.
Scheme 2. Aldehyde Fragment Synthesisa
The synthesis of aldehyde 5 began with the Ni(II)-(R)-BINAP-
catalyzed orthoester alkylation8 of thiazolidinethione 6, followed
by a subsequent Claisen condensation with ethyl hydrogen mal-
onate9 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-methyl-
ephedrine-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
a Conditions: (a) Ni-(R)-BINAP(OTf)2, 2,6-lutidine, BF3•OEt2, HC(OMe)3;
(b) HO2CCH2CO2Et, i-PrMgCl, 65 °C; (c) LiHMDS; ClPO(OEt)2; (d)
Fe(acac)3, MeMgCl, -20 °C; (e) DIBAL-H, -78 °C; (f) MnO2; (g)
Sn(OTf)2, N-ethylpiperdine, 9, -78 °C; (h) TBSOTf, 2,6-lutidine; (i) K2CO3,
MeOH; (j) OsO4, NMO; NaIO4; (k) Zn(OTf)2, (-)-N-Me-ephedrine, Et3N,
4-phenyl-1-butyne; (l) BOMCl, NaHMDS, -78 °C; (m) Lindlar catalyst,
H2; (n) K2OsO4, NMO, citric acid, 50 °C; Pb(OAc)4, K2CO3.
Scheme 3. Vinyliodide Fragment Synthesisa
a Conditions: (a) (R)-B-Me-CBS catalyst, BH3•Me2S, -30 °C; (b) KH,
H2N(CH2)3NH2, 0 °C; (c) Me3Al, Cp-2ZrCl2; I2, -45 °C; (d) TESCl,
imidazole.
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). Epimer-
ization using K2CO3 in oxygen-free methanol followed by acylation
produced salvinorin A (1), spectroscopically identical to previous
9
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J. AM. CHEM. SOC. 2007, 129, 8968-8969
10.1021/ja073590a CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Fragment Coupling and Salvinorin A Synthesisa
reinforce the desired diastereoselectivity, a fact borne out by the
experiments. This analysis also suggests that enolization favors the
Z-enolate. While this analysis presumes a stepwise process, a
concerted mechanism involving exo-selective Diels-Alder cyclo-
addition24 via the derived dipole-minimized enolate of 3 cannot be
excluded.
In conclusion, we completed the first synthesis of salvinorin A
and demonstrated the utility of a transannular reaction cascade in
the construction of polycyclic architectures. Current efforts are di-
rected toward finding epimerization conditions that favor the natural
C8 stereochemistry, probing the mechanism of the cascade reaction,
and synthesizing analogues of 1 that bear modified C12 functionality.
Acknowledgment. Support was provided by the National
Institutes of Health (GM-33327-19) and by unrestricted support
from Amgen, Merck, and Eli Lilly. The authors wish to thank Dr.
Regan Thomson for helpful suggestions.
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
a Reaction conditions: (a) n-BuLi, MgBr2•(OEt)2, -78 °C, then 5,
MgBr2•OEt2, CH2Cl2, -78 to 0 °C; (b) TBSOTf, 2,6-lutidine; (c) PPTS,
MeOH; (d) LiOH, i-PrOH, H2O; (e) MNBA, DMAP, [0.0015 M]; (f) TBAF;
(g) Dess-Martin periodinane; (h) TBAF, -78 to 5 °C; (i) NaH, Comins
reagent; (j) Pd(OAc)2, dppf, Et3SiH; (k) L-Selectride, t-BuOH, -78 to
-55 °C; (l) LiBF4, MeCN/H2O; (m) NaClO2; TMSCHN2; (n) K2CO3,
MeOH, quant. mass recovery; (o) Ac2O, py., DMAP.
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Scheme 5. Transannular Cyclization Analysis
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