Erythrophleum alkaloids. Synthesis of (–)-4-epi-cassamine

Abstract

A route for the transformation of the tricyclic podocarpenone (3) into the 4-epi-cassamine (1; R¹= H, R²= Me, R³= CO²Me, R⁴= O, R⁵= CH₂CH₂NMe₂), is reported. Elaboration of the cassane skeleton starts with the stereoselective introduction of a C-7 oxygen functionality by γ-oxidation of the dienyl acetate (4). Catalytic hydrogenation of the hydroxy enone (5a) led to a mixture of tricyclic ketones (6a)(trans-anti-cis) and (7a)(trans-anti-trans), which could be easily separated by column chromatography. They were transformed, through a route based on the regio- and stereospecific introduction of the 14-methyl group and stereoselective introduction of the methoxycarbonylmethylene group at C-13, into the epimers of methyl cassamate (18)(at C-4) and (23)(at C-4 and C-14). Transesterification of the former gave the corresponding 2-dimethylaminoethyl ester, an epimer at C-4 of the natural alkaloid cassamine.