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

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).