The generation of S-chlorocysteine proceeds with the S-protection being liberated as a cation. Removal of MBzl generally requires stronger acidity than TFA, which indicates that Cys(MBzl)(O) is not a suitable derivative for sulfenylation of Trp in proteins. A critical consideration for S-protection came from the unique chemical character of the S-Acm group that is widely used in peptide synthesis. The Acm group remains intact under highly acidic conditions. This is probably due to the formation of dicationic species resulting from dual protonation on the sulfur and amide of the S-Acm moiety. In contrast, the coordination of the sulfur atom to metals (Hg, Tl, Pd etc) or iodine under less acidic conditions results in Acm deprotection through the formation of monocationic metalated or halogenated sulfonium species (Figure ). This prompted us to hypothesize that coordination of the sulfoxide oxygen of Cys(Acm)(O) with an appropriate metal chloride under less acidic conditions might result in forming S-chlorocysteine via the oxymetalated sulfonium monocationic intermediate, which could easily release the Acm cation (Figure ). Herein we describe the development of a Trp-selective modification that proceedes under protein-friendly conditions, which is enabled by metal chloride-activated Cys(Acm)(O). This methodology has practical application to a wide variety of peptides/proteins. In addition, by taking notice of the difference in the chemical behavior between S-Acm and S-MBzl oxides in the presence of a metal chloride (Figure (ii)), we were able to create a linker that enabled the one-pot/stepwise heterodimerization of Trp-containing peptides.