Total synthesis of (±)-galanthamine and related natural products with the regioselective Pd-catalyzed coupling reactions of 3,5-dibromo-2-pyrone

초록

Galanthamine is the parent member of the galanthamine-type amaryllidaceae alkaloids, which has potent inhibitory activity against acetylcholinesterase(Ache) in CNS. It significantly enhances cognitive functions of Alzheimer’s patients and has been approved for the treatment of Alzheimer’s disease in Europe and USA. Searching for more potent inhibitors of Ache, considerable effort is directed toward its synthesis and derivatization, as it is much less toxic than other inhibitors including physostigmine and tacrine. Envisioned that the cycloadduct of properly substituted 2-pyrone can readily provide the core structure of galanthamine, we set out to investigate the total synthesis of galanthamine, using the regioselective coupling reactions of 3,5-dibromo-2-pyrone and subsequent IMDA cycloaddition reactions as key steps