Enantioselective Total Syntheses of Bisleuconothine A and Bousigonine B

Abstract

ABSTRACT Hetero‐oligomeric monoterpenoid indole alkaloids (MIAs), which possess unique three‐dimensional architectures and relatively high molecular weights, are intriguing targets in drug discovery owing to their potential to disrupt protein–protein interactions. Herein, we describe the first enantioselective total syntheses of bisleuconothine A, a dimeric MIA, and bousigonine B, a trimeric MIA. The central element of our strategy is the concise construction of a chiral 3‐ethylpiperidine scaffold, a common structural motif in MIAs. This key intermediate was prepared using a cascade sequence comprising an organocatalytic enantioselective Michael addition of a cyclic enamine to acrolein promoted by a chiral secondary amine catalyst, followed by hemiaminal cyclization and acetalization. Coupling of the aspidosperma‐ and eburnane‐type fragments, both derived from this common intermediate, was accomplished via a biomimetic Friedel–Crafts‐type reaction. The present total synthesis also revises the absolute stereochemistry of bousigonine B and constitutes the first total synthesis of a trimeric MIA.