Copper-Catalyzed Asymmetric Remote C(sp 3 )-H Alkylation of N -Fluorocarboxamides with Glycine Derivatives and Peptides.

Saturated hydrocarbon bonds are ubiquitous in organic molecules; to date, the selective functionalization of C(sp 3 )-H bonds continues to pose a notorious difficulty, thereby garnering significant attention from the synthetic chemistry community. During the past several decades, a wide array of powerful new methodologies has been developed to enantioselectively modify C(sp 3 )-H bonds that is successfully applied in asymmetric formation of diverse bonds, including C-C, C-N, and C-O bonds; nevertheless, the asymmetric C(sp 3 )-H alkylation is elusive and, therefore, far less explored. In this work, we report a direct and robust strategy to construct highly valuable enantioenriched unnatural α-amino acid (α-AA) cognates and peptides by a copper-catalyzed enantioselective remote C(sp 3 )-H alkylation of N -fluorocarboxamides and readily accessible glycine esters under ambient conditions. The key to success lies in the optically active Cu catalyst generated through the coordination of glycine derivatives to enantiopure bisphosphine/Cu(I) species, which is beneficial to the single electronic reduction of N -fluorocarboxamides and the subsequent stereodetermining alkylation. More importantly, all types (primary, secondary, tertiary, and even α-oxy) of δ-C(sp 3 )-H bonds could be site- and stereospecifically activated by the kinetically favored 1,5-hydrogen atom transfer (1,5-HAT) step.