Enantioselective total syntheses of melotenine-, voacafrine-, and tabersonine-type Aspidosperma indole alkaloids

Abstract

Although the total synthesis of aspidosperma natural products has been extensively investigated, the members possessing diverse functionalities at C3 and/or C5, which display much stronger bioactivity than the non-functionalized congeners, have not been accomplished due to the structural challenges. Herein, the first catalytic asymmetric total syntheses of C11-demethoxymelotenine, 3-oxotabersonine, voacafrine I, and 3α/3β-acetonyltabersonine are presented. Our synthesis hinged on the development of an organocatalyzed desymmetric enantioselective Michael/aldol reaction of 2-(2-nitrophenyl)cyclohexane-1,3-dione for the efficient construction of a chiral [3.3.1]-bridged bicyclic scaffold and a ring opening-reorganizing tactic of the bridged bicycle for elegant construction of a 6-5-6-5-6 pentacyclic ring system bearing functionalities amenable to distinguishable elaborations at C3, C5, and C19 positions. Utilizing the strategic polycyclic core, the enantioselective total syntheses of six previously unconquered aspidosperma-type alkaloids and stereoisomers have been achieved via a divergent manner through appropriately manipulating the functional groups at C3, C5, and C19 at the late stage.