Enantioselective Total Synthesis of (+)-Largazole, a Potent Inhibitor of Histone Deacetylase

2008-09-04T00:00:00Z (GMT) by Arun K. Ghosh Sarang Kulkarni
An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (<b>1</b>) is described. It is a potent histone deacetylase inhibitor. Our synthesis is convergent and involves the assembly of thiazole 3-derived carboxylic acid with amino ester <b>4</b> followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a β-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.