Tryptophan‐Selective Chemical Modification of Peptides by Thioether‐Mediated Sulfenylation

Chemical modification of biomolecules such as peptides and proteins is an important technology for the development of new functional molecules. Herein, a thioether‐mediated sulfenylation for tryptophan (Trp)‐selective chemical modification under mild metal‐free reaction conditions involving a weak acid/water solvent is reported. An electrophilic species generated from 4‐fluorophenyl 3‐nitro‐2‐pyridinesulfenate, Npys‐OPh( p F), in the presence of a thioether component, enables efficient sulfenylation of the Trp residue on various Trp‐containing biologically active linear and cyclic peptides. In addition, this sulfenylation to late‐stage chemical modification of a natural cyclic depsipeptide, daptomycin, is expanded and Trp‐sulfenylated derivatives, including fluorescent‐labeled derivatives, are obtained. The results indicate that the thioether‐mediated sulfenylation can be used as a robust Trp‐selective chemical modification method for peptides in a wide range of applications.