Copper-Catalyzed Enantioselective Difluoromethylation of Amino Acids via Difluorocarbene

Difluoromethyl amino acids (DFAA) exhibit intriguing biological properties, making them highly desirable motifs in agrochemical and pharmaceutical science. However, stereochemical control of direct difluoromethyl transformation via the difluorocarbene species has not been demonstrated. Here we describe an efficient copper-catalyzed asymmetric difluoromethylation reaction that systematically delivers chiral DFAA as rationally designed mechanism-based inhibitors of PLP-dependent amino acid decarboxylases. The reaction employs difluoromonochloromethane, an abundant raw material, as the direct precursor of difluorocarbene species, enabling the unprecedentedly direct conversion of amino esters into corresponding valuable DFAA products in good yields with excellent enantioselectivities. This de novo synthesis creates opportunities to integrate an asymmetric catalytic platform for the preparation of diverse libraries of biologically important DFAA derivatives and will support efforts in both drug discovery and development.