A novel synthesis of (+)-biotin from L-cysteine.

Abstract

(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis base-catalyzed cyanosilylation of alpha-amino aldehyde 3 to provide anti-O-TMS-cyanohydrin 4 with high stereoselectivity and in high yield (anti/syn = 92:8, 96%). Treatment of 4 with a di-Grignard reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the 4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic carbonate 6b that was elaborated from 5.