A Thiophilic Metal-Mediated Cysteine S‑Detritylation Strategy: Enhancing Orthogonality in Solid-Phase Peptide Synthesis.

The selective manipulation of cysteine residues in solid-phase peptide synthesis (SPPS), beyond disulfide bridge formation, remains challenging, and an efficient protocol for the selective removal of the widely used trityl (Trt) protecting group under solid-phase conditions has yet to be established. To overcome this limitation, we developed a thiophilic transition metal-mediated strategy by adapting a three-component reagent system originally conceived for solution-phase synthesis. Systematic screening of copper, zinc and silver salts identified Ag-(CF3CO2) and AgNO3 as the most effective promoters of Trt removal. The optimized protocol enabled reproducible and efficient deprotection, provided preliminary mechanistic insight through control experiments, and proved compatible with common Fmoc-SPPS protecting groups and alternative solvents. Furthermore, in situ thiol release enabled direct on-resin S-alkylation with a selected range of aliphatic substituents, including those bearing aromatic moieties, highlighting the utility of the method for the late-stage functionalization of cysteine-containing resin-bound peptides.