Architecture-Guided Sequential Editing of Distinct Disulfides in Unprotected Peptides

Abstract Disulfide modification typically relies on global reduction, preventing the selective manipulation of individual disulfide bonds within complex peptides. Here, we show that aromatic, ethyl, and tert-butyl disulfides embedded in fully unprotected peptides exhibit distinct intrinsic reactivities that can be selectively decoded by using matched activation modes. This architecture-guided hierarchy enables sequential chemoselective functionalization without the use of protecting groups. Aromatic disulfides further undergo an orthogonal phosphite-mediated transformation, expanding the repertoire of programmable disulfide editing.