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

A tyrosine (Tyr)‐ or tryptophan (Trp)‐selective metal‐free C−H sulfenylation reaction using an acid‐activated S‐acetamidomethyl 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 T...

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Published in:Chemistry : a European journal 2023-05, Vol.29 (26), p.e202300799-n/a
Main Authors: Ohkawachi, Kento, Anzaki, Kaito, Kobayashi, Daishiro, Kyan, Ryuji, Yasuda, Takuma, Denda, Masaya, Harada, Norio, Shigenaga, Akira, Inagaki, Nobuya, Otaka, Akira
Format: Article
Language:English
Subjects:
Acetamidomethyl
Chemistry
Cysteine
Cysteine - chemistry
Glucagon
Guanidine
Guanidine hydrochloride
peptide modification
Peptides
Peptides - chemistry
Residues
S-protected cysteine sulfoxide
SEAr reaction
sulfenylation
Sulfoxides
Tryptophan
Tyrosine
Tyrosine - chemistry
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Summary:A tyrosine (Tyr)‐ or tryptophan (Trp)‐selective metal‐free C−H sulfenylation reaction using an acid‐activated S‐acetamidomethyl 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. Acid test for Tyr and Trp: S‐Acetamidomethyl cysteine sulfoxide (Cys(Acm)(O)) enables the residue‐selective C−H sulfenylation of Tyr or Trp under appropriately selected acidic reaction conditions. The dicationic intermediate derived from the Cys(Acm)(O) selectively reacts with Tyr, whereas the S‐chlorocysteine allows Trp‐selective sulfenylation. The one‐pot sequence of stapling and lipidation of peptides was achieved.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202300799