Architecture-Guided Sequential Editing of Distinct Disulfides in Unprotected Peptides

Here, we show that aromatic, ethyl, and <i>tert</i>-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.