Synthesis of a Key Intermediate of Omarigliptin

Key words

omarigliptin - DPP-4 inhibitor - Meerwein–Ponndorf–Verley reduction - asymmetric enolate alkylation - iodoetherification

Significance

Wang and co-workers describe a kilogram-scale asymmetric synthesis of intermediate H en route to omarigliptin, a DPP-4 inhibitor that is of interest for the treatment of diabetes. The key steps in the synthesis depicted are (1) the dia­stereoselective substrate-controlled Meerwein–Ponndorf–Verley reduction of α-aminoketone C and (2) the stereoselective intramolecular 5-exo-dig iodoetherification of alkynol E.

Comment

Synthesis of A began with the asymmetric α-alkylation of nickel(II) complex I with 3-chloro-1-propyne. The choice of solvent and temperature was critical to achieve a reproducible conversion and high stereoselectivity for this alkylation. Best results were obtained using sodium hydroxide in DMF at –10 °C. At the end of the reaction, water was added to the reaction mixture, and product J crystallized out from the aqueous media.