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

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 structurallydiverse 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 His, Trp and Tyr, and can be used for the functionalization of biologically relevant peptides, as exemplified by the late-stage modification of a semaglutide analogue and the preparation of high-value macrocyclic peptides.