A Concise Total Synthesis of (+)-Tetrabenazine and (+)-alpha-Dihydrotetrabenazine

Abstract

Highly concise asymmetric total syntheses of (+)-tetrabenazine (1), a drug for the treatment of chorea associated with Huntington's disease, and of (+)-alpha-dihydrotetrabenazine (2), an active metabolite of 1, have been accomplished. Our synthetic route features a trans-selective enol etherification, followed by an unprecedented cation-dependent aza-Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34% overall yield) for (+)-2 and eight steps (22% overall yield) for (+)-1.