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(pF), 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.