19. Divergent Total Syntheses of (−)-Huperzine Q, (+)-Lycopladine B, (+)-Lycopladine C, and...

We report herein our synthetic efforts towards the divergent syntheses of (−)-huperzine Q (1), (+)-lycopladine B (2), (+)-lycopladine C (3), and (−)-lycopladine D (4). The 10-step total synthesis of (−)-huperzine Q (1) and the first total syntheses of (+)-lycopladines B (2) and C (3) were accomplished through a series of cascade reactions. Our approach involved a Michael addition/aldol/intramolecular C-alkylation sequence to forge the 6/9 spirocycle ring, and this was followed by an ethylene-accelerated carbonyl–olefin metathesis to construct the common 6/5/9 ring system. Finally, late-stage enamine bromofunctionalization enabled us to access (−)-huperzine Q (1), (+)-lycopladine B (2), and (+)-lycopladine C (3), and a tandem C4-epimerization/retro-Claisen condensation furnished (−)-4-epi-lycopladine D (63).