Residue-selective C−H sulfenylation enabled by acid-activated S-acetamidomethyl cysteine sulfoxide with application to one-pot stapling and lipidation sequence

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  • Residue‐Selective C−H Sulfenylation Enabled by Acid‐Activated <i>S</i>‐Acetamidomethyl Cysteine Sulfoxide with Application to One‐Pot Stapling and Lipidation Sequence

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A tyrosine (Tyr)- or tryptophan (Trp)-selective metal-free C−H sulfenylation reaction using an acid-activated Sacetamidomethyl cysteine (Cys) sulfoxide, Cys(Acm)(O), has been achieved. The dually protonated intermediate produced from the 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-Trplinked 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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