Photocatalytic Carbamoylation to Access Thiocarbonyl Amino Acid/Peptide Derivatives in Sustainable Solvent

Abstract

The development of sustainable methods for peptide modification and sulfur incorporation remains a central challenge in chemical biology and catalysis. Here, we first report a visible-light-promoted, metal-free carbamoylation strategy that enables the direct synthesis of thiocarbonyl amino acid and peptide derivatives from DHP-tagged amino acids and peptides.This transformation proceeds via a photocatalytic radical process that forms C-S bonds efficiently under mild, biocompatible conditions. The method features a broad substrate scope and high functional group tolerance, delivering over 50 examples up to 98% yield. Mechanistic studies support the generation of carbamoyl radicals from 4-carbamoyl-DHP precursors, followed by selective coupling with thiolations to furnish the corresponding thiocarbonyl products. The reaction operates smoothly at room temperature, employs green solvents, and can be readily scaled up without loss of efficiency. Furthermore, this protocol enables the late-stage functionalization of amine-containing drugs, natural products, and proteins, providing a general and sustainable platform for peptide diversification.