Synthetic Studies on Enantioselective Total Syntheses of Tabercarpamines and Voacangine-Type Indole Alkaloids

Abstract

The proposed post-iboga natural products, (+)-tabercarpamines G and I, along with their corresponding C20 stereoisomers and C10-methoxy-regioisomers were synthesized. An extensive NMR spectroscopic study showed that the spectral data of these synthetic compounds were not consistent with the proposed (+)-tabercarpamines G and I in isolation report, indicating that the proposed structures were misassigned. Subsequently, from the advanced intermediates for the synthesis of the proposed (+)-tabercarpamines G and I, the unified enantioselective syntheses of six iboga‒type natural products including (-)-isovoacangine and (-)-voacangine, (-)-3-oxo-isovoacangine and (-)-3-oxo-voacangine, and (-)-(3S)-cyanoisovoacangine and (-)-(3S)-cyanovoacangine were accomplished via a divergent manner. The synthetic route provided the first catalytic asymmetric approach to access these three types of iboga‒type natural products and achieved the first enantioselective syntheses of (3S)-cyano(iso)voacangines. Our synthesis hinged on a catalytic asymmetric Michael/aldol reaction for the construction of chiral aza-[3.3.1]-bridged bicyclic framework at the early stage and a ring reorganization process from [3.3.1]- to [2.2.2]-bicyclic ring system-a pathway opposite to the proposed biogenic synthesis-at the late stage.

Keywords: Michael/aldol cascade; iboga natural product; phase transfer catalysis; ring reconstruction; total synthesis.