Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75-92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)-and (S)-1-phenylethylamines, the partially enantioenriched (R)-and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided > 99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.

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