Enantioselective Total Syntheses of Bisleuconothine A and Bousigonine B

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.