Development of a Practical Synthesis of DPP IV Inhibitor LY2497282

A new synthetic route to LY2497282 (1), a potent and selective DPP IV inhibitor for the potential treatment of diabetes, suitable for the preparation of multikilogram quantities is described. The key step involved a stereoselective addition of the dianion of nicotinamide 8 to N-dibenzyl-protected α-amino aldehyde 12, which was derived from N-acetyl-protected amino ester 14 without epimerization. The desired Felkin-Anh nonchelation controlled anti-amino alcohol 11 was isolated with >99% HPLC area and >99% ee by crystallization. After removing the dibenzyl protecting group under transfer hydrogenation conditions, LY2497282 (1) was finally obtained in 39% overall yield with a six-step longest linear sequence starting from N-acetyl-protected amino ester 14.