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

• Published in: Chemistry : a European journal 2021-10, Vol.27 (56), p.14092-14099
• Main Authors: Kobayashi, Daishiro, Kohmura, Yutaka, Sugiki, Toshihiko, Kuraoka, Eisuke, Denda, Masaya, Fujiwara, Toshimichi, Otaka, Akira
• Format: Article
• Language: English
• Subjects: Anions; Biological activity; Chemistry; Crosslinking; Cysteine; Disulfide bonds; Guanidine hydrochloride; Methanesulfonic acid; Nucleophiles; Oxidation; peptide cyclization; Peptides; S-arylation; stapling; Substitution reactions; Sulfoxides; Triflic acid; tryptathionine; Tryptophan
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202102420

Covalent linking of side chains provides a method to produce cyclic or stapled 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 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 a thioether linkage between tryptophan 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 stapled 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 a Cys nucleophile and is useful for S‐arylation‐mediated peptide cyclization. Acid‐mediated activation of an S‐protected cysteine sulfoxide allows for the cyclization of peptides through metal‐free C−H sulfenylation of arenes. The less electrophilic S‐p‐methoxybenzyl cysteine sulfoxide serves as an acid‐activated umpolung of nucleophilic cysteine in the presence of guanidine hydrochloride under acidic conditions. It is useful for S‐arylation‐mediated peptide cyclization, which results in the synthesis of an Amatoxin derivative and stapled peptide possessing a tryptathionine structure.