Enantioselective Total Syntheses of (-)-20-epi-Vincamine and (-)-20-epi-Eburnamonine by Ir-Catalyzed Asymmetric Imine Hydrogenation/Lactamization Cascade

Abstract

The Eburnamine-Vincamine alkaloids have been studied intensively over the past six decades for their outstandingly potent vasorelaxation activity. Stereocontrolled assembly of the C20/C21 adjacent chiral centers has been a formidable challenge in the synthesis of this family. Herein, we report a concise stereoselective total synthesis of two trans-ring-fused non-natural analogues, (-)-20-epi-Vincamine and (-)-20-epi-Eburnamonine, that features the following key steps: a) a continuous-flow oxidation/lactam alcoholysis cascade producing the symmetrical dihydro-β-carboline diester precursors, and b) a highly stereoselective Ir/f-Binaphane-catalyzed hydrogenation/lactamization cascade leading to the privileged trans-(20R, 21S) lactam ester scaffold with high-level enantio- and diastereocontrol.

Keywords: continuous-flow; eburnamine-vincamine alkaloids; hydrogenation/lactamization cascade; total synthesis; trans-selectivity.