Late-​stage solubilization of poorly soluble peptides using hydrazide chemistry

Kohei Sato*, Shoko Tanaka, Junzhen Wang, Kenya Ishikawa, Shugo Tsuda, Tetsuo Narumi, Taku YoshiyaTaku Yoshiya

Org. Lett. 2021, 23, 1653–1658. 

A novel late-stage solubilization of peptides using hydrazides is described. A solubilizing tag was attached through a selective N-alkylation at a hydrazide moiety with the aid of a 2-picoline–borane complex in 50% acetic acid–hexafluoro-2-propanol. The tag, which tolerates ligation and desulfurization conditions, can be detached by a Cu-mediated selective oxidative hydrolysis of the N-alkyl hydrazide. This new method was validated through the synthesis of HIV-1 protease.