The aromatic (C−H) sulfenylation reaction with S‐acetamidomethyl cysteine sulfoxide (Cys(Acm)(O)) can be Trp‐ or Tyr‐selective under acidic conditions. The red chloride anion team kicks the Cys(Acm)(O) ball into the Trp goal, whereas the blue trimethylsilyl team kicks the ball into the Tyr goal. The proton scoreline in the stands supports both teams. More information can be found in the Research Article by A. Otaka and co‐workers (DOI: 10.1002/chem.202300799).
A tyrosine (Tyr)-or tryptophan (Trp)-selective metalfree CÀ H sulfenylation reaction using an acid-activated Sacetamidomethyl cysteine (Cys) sulfoxide, Cys(Acm)(O), has been achieved. The dually protonated intermediate produced from Cys(Acm)(O) under acidic conditions allows the sulfenylation of Tyr. Significantly, the reaction in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) mainly affords a Cys-Tyr-linked peptide even in the presence of Trp residues. In contrast, a Cys-Trp-linked peptide was selectively obtained from the reaction in the presence of guanidine hydrochloride (Gn • HCl) under acidic conditions. Established Tyr-and Trp-selective sulfenylation methods were used in the Cys-Tyr stapling and Trp lipidation of glucagon-like peptides 1 in a one-pot/stepwise manner. Investigation of the mechanism showed that orbital-and charge-controlled reactions are responsible for the Trp and Tyr selectivity, respectively.
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