Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161

A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60. Matteson homologations and a Pd-catalysed C-H functionalisation are key steps in the synthesis of highly selective HDAC1 inhibitor WF-3161.