Enantioselective Synthesis of (R)-Sitagliptin via Phase-Transfer Catalytic aza-Michael Addition

초록

The highly enantioselective synthesis of (R)-sitagliptin has been achieved through a series of key steps, including the aza-Michael addition and Baeyer-Villiger oxidation. The enantioselective aza-Michael addition involved the reaction of tert-butyl β-naphthylmethoxycarbamate with (E)-1-(4-methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one, utilizing a quinine-derived C(9)-urea ammonium catalyst under phase-transfer catalytic conditions. The aza-Michael addition successfully introduced chirality to the amine in (R)-sitagliptin with 96% ee. The subsequent Baeyer-Villiger oxidation of the aza-Michael adduct led to the formation of 4-methoxyphenyl ester. Hydrolysis and amide coupling were then employed to construct the amide moiety. Further deprotections were performed to complete the synthesis of (R)-sitagliptin (7 steps, 41%, 96% ee). © 2024 The Authors. Published by American Chemical Society

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