Wang Yafang, Song Changying, Xing Yueyue, Shen Shigang, Bo Tianyu, Zhang Nan, Wang Jixu, Shi Tiesheng, Huo Shuying
College of Chemistry and Materials Science, Key Laboratory of Analytical Science and Technology of Hebei Province, and MOE Key Laboratory of Medicinal Chemistry and Molecular Diagnostics, Hebei University, Baoding 071002, Hebei Province, China.
College of Chemistry, Chemical Engineering and Materials Science, Zaozhuang University, Zaozhuang 277160, Shandong Province, China.
J Org Chem. 2023 Jul 7;88(13):8123-8132. doi: 10.1021/acs.joc.3c00104. Epub 2023 May 26.
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.
在合成肽化学中，肽中多个二硫键的区域选择性合成一直是一项重大挑战。在这项工作中，通过甲硫氨酸亚砜（MetSeO）氧化和脱保护反应（SeODR）方法区域选择性地合成了肽中的两个二硫键，其中第一个二硫键是通过在中性缓冲液中用MetSeO氧化二硫醇构建的，然后第二个二硫键是通过在酸性介质中用MetSeO对两个Acm基团或一个Acm基团和一个Thz基团进行脱保护直接构建的。通过SeODR方法合成两个二硫键是以一锅法实现的。此外，SeODR方法与含甲硫氨酸残基的肽的合成兼容。H和Br都极大地促进了SeODR的反应速率。描绘了SeODR方法的机理图，其中作为过渡态的稳定Se-X-S桥的形成起着关键作用。SeODR方法还被用于构建利那洛肽中的三个二硫键，并获得了合理的产率。
