N-Halosuccinimides mediated deprotection of cysteine-S protecting groups for one-pot regioselective synthesis of disulfide bonds in peptides under mild aqueous conditions

• Published in: Tetrahedron letters Vol. 120; p. 154459
• Main Authors: Xing, Yueyue, Wang, Yafang, Ma, Dongying, Shen, Shigang, Song, Changying, Zhang, Nan, Bo, Tianyu, Shi, Tiesheng, Huo, Shuying
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 28-04-2023
• Subjects: Deprotection; Multiple disulfide bonds; N-halosuccinimides; One-pot synthesis; Peptides; One-pot synthesis; N-halosuccinimides; Multiple disulfide bonds; Peptides; Deprotection
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2023.154459

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•Two disulfide bonds were synthesized regioselectively by an one-pot approach.•Good yield was achieved under mild conditions.•Formation of a hydrolytic stable halosulfonium cation plays a critical role in the reactions.
Cysteine (Cys) with side chain protected by groups acetamidomethyl (Acm), 1,3-thiazolidine-4-carbonyl (Thz) and t-butyl (tBu) has been commonly used for the synthesis of correct disulfide bonds in peptides. Deprotection of these protected groups can be achieved by use of metal salts under harshly removing conditions. In this work, N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS) are demonstrated to deprotect these protecting groups to directly form an intramolecular disulfide bond in peptide. In addition, all the deprotection reactions were complete within 10 min, conferring fast reaction rates. Moreover, formation of a hydrolytic stable halosulfonium cation was revealed to play a critical role in these deprotection reactions. When NCS and NBS were employed for deprotecting these groups, two disulfide bonds in α-conotoxin SI, α-conotoxin IMI and apamin were synthesized regioselectively by an one-pot approach, rendering satisfied yields.