Highly Enantioselective Synthesis of Sitagliptin

A highly enantioselective synthesis of sitagliptin, a potent DPP‐4 inhibitor, is reported. Explicitly identified chiral FerroLANE ligands in the presence of rhodium catalyze the asymmetric hydrogenation of an enamine to yield sitagliptin with excellent enantioselectivity (98% ee). The process was scaled up to 5 g and the final product was isolated as a phosphate salt with >99% ee. The asymmetric hydrogenation of a precursor enamine to sitagliptin has been investigated and initial screening indicated FerroLANE ligands as suitable candidates. Thus, a Rh‐FerroLANE catalyzed, highly enantioselective (>99%) synthesis of sitagliptin, a potent DPP‐4 inhibitor, has been reported. The synthetic utility of the process has been demonstrated by scaling the reaction to 5 g and by isolating sitagliptin in its stable form.