Advanced Insulin Synthesis by One‐pot/Stepwise Disulfide Bond Formation Enabled by S‐Protected Cysteine Sulfoxide

Abstract

AbstractAn advanced insulin synthesis is presented that utilizes one‐pot/stepwise disulfide bond formation enabled by acid‐activated S‐protected cysteine sulfoxides in the presence of chloride anion. S‐chlorocysteine generated from cysteine sulfoxides reacts with an S‐protected cysteine to afford S‐sulfenylsulfonium cation, which then furnishes the disulfide or reversely returns to the starting materials depending on the S‐protection employed and the reaction conditions. Use of S‐acetamidomethyl cysteine (Cys(Acm)) and its sulfoxide (Cys(Acm)(O)) selectively give the disulfide under weak acid conditions in the presence of MgCl2 even if S‐p‐methoxybenzyl cysteine (Cys(MBzl)) and its sulfoxide (Cys(MBzl)(O)) are also present. In contrast, the S‐MBzl pair yields the disulfide under more acidic conditions in the presence of a chloride anion source. These reaction conditions allowed a one‐pot insulin synthesis. Additionally, lipidated insulin was prepared by a one‐pot disulfide‐bonding/lipidation sequence.