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 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.

This is the peer reviewed version of the following article: Ohkawachi, Kento, Anzaki, Kaito, Kobayashi, Daishiro, Kyan, Ryuji, Yasuda, Takuma, Denda, Masaya, Harada, Norio, Shigenaga, Akira, Inagaki, Nobuya, Otaka, Akira, Chem. Eur. J. 2023, 29, 26, e202300799., which has been published in final form at https://doi.org/10.1002/chem.202300799. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.