Protein modification alters structure and reactivity by adding non-native groups to specific residues. For most nucleophilic residues, multiple functionalization methods have been reported. However, there are limited methods that take advantage of the unique reactivity of methionine residues. We exploited this reactivity profile of methionine by using a strained reactive intermediate selective for thioethers. To optimize the reaction in aqueous conditions, we altered the structure of the reactive intermediates’ precursors to increase their solubility in water, while preserving reactivity. We show that these reactive intermediates can be generated under mild conditions allowing for the preservation of peptide and protein structures. The strategy was successfully applied to a variety of natural products, peptides, and proteins. Additionally, we demonstrated the one-pot sulfonium formation then demethylation, which afforded the functionalized homocysteine product. The development of this site-selective method towards methionine will allow for valuable modifications of complex molecules in mild conditions.
