Synthesis of Salvinorin A

doi:10.1055/s-2007-991305

Synfacts 2007(12): 1225-1225
DOI: 10.1055/s-2007-991305

Synthesis of Natural Products and Potential Drugs

Synthesis of Salvinorin A

Rezensent(en):Philip Kocienski, Stewart Eccles

J. R. Scheerer, J. F. Lawrence, G. C. Wang, D. A. Evans*
Harvard University, Cambridge, USA
Asymmetric Synthesis of Salvinorin A, A Potent κ Opioid Receptor Agonist
J. Am. Chem. Soc. 2007, 129: 8968-8969

Abstract

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Key words

bis-Michael addition - macrolactonization -

Significance

Salvinorin A is a neoclerodane diterpene isolated from Salvia divinorum. As a potent agonist of the κ opioid receptor, it is the only non-alkaloid psychoactive substance and the most potent naturally occuring hallucinogen. The synthesis of salvinorin exploits a bis-Michael addition of macrocylce E to create the tricyclic core. A rich array of innovative chemistry was used to synthesise fragment B.

Comment

The 14-membered macrolactone E was produced at very low concentrations (0.0015 M) using MNBA to produce a mixed anhydride which cyclized in very good yield (96%). The transannular bis-Michael addition of E promoted by TBAF was proposed to go via the transition state F to give the correct stereochemistry in G. It was also suggested that a concerted exo-selective Diels-Alder reaction would result in the correct product.

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