Chiral Lewis Base-Catalyzed, Enantioselective Reduction of Unprotected β-Enamino Esters with Trichlorosilane

Catalytic asymmetric reduction of N-unsubstituted beta-enamino esters represents a major challenge for asymmetric catalysis. In this paper, the first organocatalytic system that could be used for the asymmetric hydrosilylation of N-unsubstituted beta-enamino esters has been developed. Using N-tert-butylsulfinyl-L-proline-derived amides and L-pipecolinic acid-derived formamides as catalyst, a broad range of beta-aryl- and beta-alkyl-substituted free beta-amino esters could be prepared with high yields and enantioselectivities. The practicality was illustrated by the gram-scale asymmetric synthesis of ethyl (R)-3-amino-3-phenylpropanoate and isopropyl (S)-3-amino-4-(2,3,5-trifluorophenyl)butanoate. The resulting product can be smoothly transformed to the FDA approved medicines dapoxetine and sitagliptin in a short synthetic route.