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

ACS Omega

Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.

Published: April 2024

The highly enantioselective synthesis of ()-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 -butyl β-naphthylmethoxycarbamate with ()-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 ()-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 ()-sitagliptin (7 steps, 41%, 96% ee).

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10993359PMC
http://dx.doi.org/10.1021/acsomega.3c10080DOI Listing

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