Harnessing the Reactivity of Sulfinate Salts With Cystine: An Umpolung Approach to Residue‐Specific Peptide Modification

Abstract

ABSTRACT The first use of sulfinate salts for the late‐stage modification of peptidic disulfide bonds is reported. While the majority of cysteine‐based peptide modifications rely on the nucleophilicity of the side chain thiol functionality, umpolung approaches—exploiting instead the electrophilicity of the cystine disulfide—are underexplored. Using structurally diverse sulfinate salts, we have optimized a mild, photochemical strategy for the generation and coupling of carbon‐centered radicals with both symmetrical and electronically‐distinct, unsymmetrical cystine disulfides using high‐throughput experimentation techniques. A library of modified peptides was accessible, as confirmed by qualitative and quantitative analytical data, providing valuable insights into the matched reactivity of specific radical/disulfide substrate pairings. The method was broadly compatible with a range of unprotected amino acids, including histidine, tryptophan, and tyrosine, and can be used for the functionalization of biologically relevant peptides, as exemplified by the selective, late‐stage modification of a semaglutide analogue and the preparation of high‐value macrocyclic peptides.