Org Lett 2018 06 6;20(12):3695-3699. Epub 2018 Jun 6.
Novo Nordisk Research Center Indianapolis , Indianapolis , Indiana 46241 , United States.
A simplified route to synthesis of INSL5 is reported, where the elimination of intermediate purification steps and nonconventional disulfide pairing results in final yields that are an order of magnitude higher than in previously reported stepwise syntheses. The intramolecular disulfide of A-chain was produced by a thiol displacement of StBu-protected cysteine, and was followed by an A-B chain disulfide formation in dimethylsulfoxide (DMSO). The final disulfide was formed by deprotection of StBu-cysteines in hydrofluoric acid (HF) at room temperature, which is a historical approach infrequently employed today, followed by oxidation using 2,2-dithiobis(5-nitropyridine) (DTNP) in acidic aqueous buffer. Throughout the synthesis, an isoacyl surrogate to a midsequence native amide bond was utilized to enhance solubility of the intermediate compounds.