Total synthesis of (+)-himbacine and (+)-himbeline

Himbacine (1), a complex piperidine alkaloid isolated from the bark of Aust ralian magnolias, is a promising lead in Alzheimer's disease research due t o its potent muscarinic receptor antagonist property. We have described her e a highly efficient synthetic strategy that resulted in the total synthesi s of himbacine (1) in about 10% overall yield and isohimbacine (la), an unn atural isomer of himbacine, in 18% overall yield. The total synthesis of hi mbacine was initially approached using an intramolecular Diels-Alder reacti on as the key step to generate intermediate 5 followed by a [3 + 2] cycload dition with nitrone 4 to produce the isoxazolidine derivative 3. Methylatio n followed by catalytic reduction of 3 gave 12'-hydroxyhimbacine (20), whic h, upon dehydration, gave isohimbacine (la) as the sole product. In an alte rnative approach, an all-encompassing intramolecular Diels-Alder reaction o f an appropriately substituted tetraene derivative 31, which bears the enti re latent carbon framework and functional group substitution of himbacine, gave the desired advanced tricyclic intermediate 33, which was readily conv erted to (+)-himbeline (2) and (+)-himbacine (1).