Copper-Catalyzed Asymmetric Remote C(sp<sup>3</sup>)–H Alkylation of <i>N</i>-Fluorocarboxamides with Glycine Derivatives and Peptides
Wei Wang, Liangming Xuan, Qinlin Chen, Rundong Fan, Fei Zhao, Jianghu Dong, Haifeng Wang, Qiongjiao Yan, Hui Zhou, Fen‐Er Chen
Abstract
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.