l‑Methionine Selenoxide as an Oxidizing and Deprotection Reagent for the Synthesis of Multiple Disulfide Bonds in Peptides

• Published in: Journal of organic chemistry Vol. 88; no. 13; pp. 8123 - 8132
• Main Authors: Wang, Yafang, Song, Changying, Xing, Yueyue, Shen, Shigang, Bo, Tianyu, Zhang, Nan, Wang, Jixu, Shi, Tiesheng, Huo, Shuying
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07-07-2023
• Subjects: Disulfides - chemistry; Indicators and Reagents; Methionine - chemistry; Methionine - metabolism; Oxidation-Reduction; Peptides - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c00104

The regioselective synthesis of multiple disulfide bonds in peptides has been a significant challenge in synthetic peptide chemistry. In this work, two disulfide bonds in peptides were regioselectively synthesized via an approach of MetSeO oxidation and deprotection reaction (SeODR), in which the first disulfide bond was constructed through oxidation of dithiol by MetSeO in a neutral buffer, and the second disulfide bond was then directly constructed through the deprotection of two Acm groups or one Acm group and one Thz group by MetSeO in acidic media. Synthesis of two disulfide bonds by the SeODR approach was achieved through a one-pot manner. Moreover, the SeODR approach is compatible with the synthesis of peptides containing methionine residues. Both H+ and Br– drastically promoted the reaction rate of SeODR. The mechanistic picture for the SeODR approach was delineated, in which the formation of a stable Se–X–S bridge as the transition state plays a critical role. The SeODR approach was also utilized to construct the three disulfide bonds in linaclotide, conferring a reasonable yield.