Total Synthesis of Largazole and Its Biological Evaluation

Abstract

We achieved a total synthesis of largazole. The optically active β-hydroxycarbonyl unit was prepared from a modified Nagao’s N-acetylthiazolidinethione. A 4-methylthiazoline-thiazole amino ester was prepared by both a step-by-step method and tandem cyclization from Cys-2-MeCys-containing tripeptide. Amidation of the activated β-hydroxycarbonyl unit and 4-methyl-thiazoline-thiazole-containing amino ester, followed by esterification with N-Fmoc valine afforded cyclization precursor after selective removal of the methyl ester at the C-terminus and the Fmoc group at the N-terminus. Macrolactamization, deprotection of thiol, and S-acylation provided largazole. Biological evaluation of its S-modified derivatives as well as the synthetic largazole exhibited strong inhibitory activity against histone deacetylases (HDAC).