Copper-Photoredox-Catalyzed Divergent Strategy for the Site-selective Arylation and Alkylation of Glycines and peptides

Abstract

There is a scarcity of general strategies for the site-selective α-Csp3-H arylation of glycine derivatives to synthesize non-proteinogenic α-arylglycines that occur frequently in commercial drugs and bioactive molecules. We disclose a copper-photoredox catalyzed site-selective α-Csp3-H arylation of glycine derivatives using diaryliodonium reagents (DAIRs) as aryl transfer agents. This strategy harnesses the underexplored ability of copper catalysts to generate aryl radicals from DAIRs under sustainable conditions. The method applies to the glycine-selective C-H arylation of peptides with electronically and structurally diverse DAIRs. Moreover, we demonstrate that the photoinduced copper-catalyzed single electron transfer (SET) strategy can be coupled with the halogen atom transfer (XAT) process in the presence of alkyl iodides to accomplish site-selective α-Csp3-H alkylation of glycines and peptides. In this synergistic SET/XAT approach, phenyl radicals generated from diphenyl iodonium triflate mediate the XAT process to generate alkyl radicals from alkyl iodides. Both these methods operate under mild and sustainable conditions and exhibit broad scope with appreciable functional group tolerance. Overall, the presented divergent toolbox strategies facilitate access to various alkylated and arylated glycines and peptides and enable bioconjugation between peptides and drug molecules.