Selenoimidazolium Salts as Supramolecular Reagents for Protein Alkylation

Se‐benzyl selenoimidazolium salts are characterized by remarkable alkyl‐transfer potential under physiological conditions. Structure‐activity relationship studies show that selective monoalkylation of primary amines depends on supramolecular interactions between the selenoimidazole leaving group and the target nucleophile. We demonstrate that these reagents can be used for site‐selective and nearly quantitative modification of the model protein lysozyme on Lys13, bypassing the higher intrinsic reactivities of Lys1 and Lys33. These observations introduce selenoimidazolium salts as novel class of electrophiles for selective N‐alkylation of native proteins. Smart leaving groups: Selenoimidazolium salts leverage supramolecular interactions for selective covalent modification of proteins. SAR studies show that interactions with the N‐benzyl side chains of the electrophile are important to recognize and activate the specific nucleophilic substrate. Selenoimidazoles′ modular structure and simple synthesis bode well for developing second‐generation supramolecular reagents that could alkylate specific residues in other proteins of interest.