A kilogram scale enantioselective synthesis of the axially chiral 11-β-HSD inhibitor, BMS-816336 (1) is described, enabling rapid access to this drug candidate. Starting from 2,6-adamantanedione (3), the molecule’s two symmetrical ketones are differentiated by a selective mono-deketalization. The key all-carbon quaternary center is then formed using a Grignard addition, Friedel-Crafts alkylation sequence, leading to a prochiral intermediate (2). The target molecule’s axial chirality is established using an enzymatic ketone reduction, then elaborated to BMS-816336 (1) via amide coupling.

Efficient and scalable enantioselective synthesis of the axially chiral 11-β-HSD inhibitor, BMT-816336

253rd National Meeting (2017)

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