Direct Editing of Cysteine to Electrophilic Alkyl Halides in Peptides

Functional group conversion is a cornerstone of modern synthetic chemistry. Many strategies routinely employed for small-molecule transformations are unsuitable for modifying biomacromolecules, including peptides. Here, we describe a simple but chemoselective approach that directly converts the nucleophilic cysteine carbon–thiol side chain into an electrophilic carbon–halogen bond under mild conditions, compatible with diverse peptides. The incorporation of this versatile synthetic handle facilitates a range of subsequent transformations that are rarely, if ever, applied to complicated peptides. We envision that this side-chain editing methodology will open a broad expanse of unexplored peptide chemical space, which will concomitantly unlock applications for an entire class of new biomacromolecules.