Copper-Catalyzed Asymmetric Remote C(sp³)–H Alkylation of N-Fluorocarboxamides with Glycine Derivatives and Peptides

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 coppercatalyzed 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.

An aryl-to-alkyl radical relay arylation reaction of a remote C(sp3)–H bond using 1,4-dicyanobenzene as an electrochemical redox-mediator

“…2 For directing group enabled C(sp 3 )–H bond functionalizations, a radical-mediated intermolecular 1,5-hydrogen atom transfer (HAT) strategy provides a platform for remote unactivated C–H functionalization transformations. 3 In particular, an aryl radical, a transient radical intermediate, could be used not only for constructing various C–C and C–X bonds but also to perform more challenging transformations, such as remote C–H functionalization reactions via aryl-to-alkyl radical relays. 4 In the 1990s, Curran 5 introduced the novel concept of free radical translocation from a transient aryl radical to an alkyl radical via a 1,5-HAT process.…”