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

Abstract

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.

Recent Advances in Metal-Free Peptide Stapling Strategies

“…In a further research, they reported that S-Acetamidomethyl cysteine sulfoxide (Cys-(Acm)(O)) could selectively make C−H sulfenylation of Tyr or Trp under suited acidic conditions (Scheme 10C). 68 The amide of the Acm group and the sulfoxide will achieve protonation by the acidic trimethylsilyl trifuluoromethanesulfonate (TMSOTf), resulting in the formation of a dicationic species which selectively reacts with Tyr, whereas the Schlorocysteine allows Trp-selective sulfenylation in the presence of Gn•HCl.…”

“…In the reaction between Cys­(MBzl)­(O) and Trp to form Cys-Trp thioether bonds, strong acids such as trifluoromethanesulfonic acid (TFMSA) or methanesulfonic acid (MSA) are required in the presence of guanidine hydrochloride (Gn·HCl) to activate sulfoxides, generating electrophilic Cys derivatives that bind to indole through aromatic electrophilic substitution. In a further research, they reported that S-Acetamidomethyl cysteine sulfoxide (Cys­(Acm)­(O)) could selectively make C–H sulfenylation of Tyr or Trp under suited acidic conditions (Scheme C) . The amide of the Acm group and the sulfoxide will achieve protonation by the acidic trimethylsilyl trifuluoromethanesulfonate (TMSOTf), resulting in the formation of a dicationic species which selectively reacts with Tyr, whereas the S-chlorocysteine allows Trp-selective sulfenylation in the presence of Gn·HCl.…”

Hexafluoroisopropanol as a Bioconjugation Medium of Ultrafast, Tryptophan-Selective Catalysis

“…There has been continuous interest in the utilization of indole rings in the organic and medicinal chemistry fields for over a hundred years, and tryptophan-targeted labeling in proteins having been attempted even in the early 20th century . A set of indole-selective chemical reactions were examined as tryptophan-targeting methods for proteins in organic solvents, − although organic solvents are generally incompatible with protein substrates (Figure A,B). More recently, elegant tryptophan-selective chemical labeling in an aqueous environment was achieved through a rhodium-catalyzed diazo decomposition reaction, amine oxide-based radical addition, iron-assisted radical trifluoromethylation, or photoinduced electron transfer-based carbamylation .…”

Late-Stage Formation of a Sactionine Linkage Enabled by Lossen Rearrangement of Glycyl Hydroxamic Acid

“…Initially, we examined the reaction of 11 in TFA (Figure S9), which proceeded slowly to yield the desired sactionine linkage-containing peptide 12 , but also non-negligible amounts of byproducts modified by the Acm cation, which was released as the thioether-forming reaction proceeded. Because guanidine can trap acyl iminium-type cations such as the Acm cation, , we tested the addition of guanidium salt to the reaction mixture to trap the cation, despite the possibility that the acid-activated Gly­(OH) moiety might also be trapped by guanidine. Among various guanidine salts tested, including Gn·HCl, Gn·HOTf, and (Gn) 2 ·H 2 SO 4 , Gn·HCl showed the best performance in that the reaction proceeded not only without side reactions but also with fast reaction kinetics (Figure S9).…”