Peptide Cyclization Mediated by Metal-Free S-Arylation : S-Protected Cysteine Sulfoxide as an Umpolung of the Cysteine Nucleophile

Covalent linking of side chains provides a method to produce cyclic or stapling peptides that are important in developing peptide-based drugs. A variety of crosslinking formats contribute to fixing the active conformer and prolonging its biological activity under physiological conditions. One format uses the cysteine (Cys) thiol to participate in crosslinking through nucleophilic thiolate anions or thiyl radicals to form thioether and disulfide bonds. Removal of the S-protection from an S-protected Cys derivative generates the thiol which functions as a nucleophile. S-Oxidation of a protected Cys allows the formation of a sulfoxide that operates as an umpolung electrophile. Herein, the applicability of S-p-methoxybenzyl Cys sulfoxide (Cys(MBzl)(O)) to the formation of thioether linkage between tryptophan (Trp) and Cys has been investigated. The reaction of peptides containing Cys(MBzl)(O) and Trp with trifluoromethanesulfonic acid (TFMSA) or methanesulfonic acid (MSA) in TFA in the presence of guanidine hydrochloride (Gn·HCl) proceeded to give cyclic or stapling peptides possessing the Cys–Trp thioether linkage. In this reaction, strong acids such as TFMSA or MSA are necessary to activate the sulfoxide. Additionally, Gn·HCl plays a critical role in producing an electrophilic Cys derivative that combines with the indole by aromatic electrophilic substitution. The findings led us to conclude that the less electrophilic Cys(MBzl)(O) serves as an acid-activated umpolung of Cys nucleophile and is useful for S-arylation-mediated peptide cyclization.

This is the peer reviewed version of the following article: Kobayashi, D., Kohmura, Y., Sugiki, T., Kuraoka, E., Denda, M., Fujiwara, T. and Otaka, A. (2021), Peptide Cyclization Mediated by Metal-Free S-Arylation: S-Protected Cysteine Sulfoxide as an Umpolung of the Cysteine Nucleophile. Chem. Eur. J. 2021, 27, 14092., which has been published in final form at https://doi.org/10.1002/chem.202102420. 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.