Macrolactamization versus Macrolactonization: Total Synthesis of FK228, the Depsipeptide Histone Deacetylase Inhibitor†

Wen, S, Packham, G and Ganesan, A (2008) Macrolactamization versus Macrolactonization: Total Synthesis of FK228, the Depsipeptide Histone Deacetylase Inhibitor†. The Journal of Organic Chemistry, 73 (23). pp. 9353-9361. ISSN 0022-3263

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Abstract

The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
University of East Anglia > Faculty of Science > Research Groups > Medicinal Chemistry
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Depositing User: Deborah Clemitshaw
Date Deposited: 20 Oct 2011 12:16
Last Modified: 25 Jul 2018 05:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/35114
DOI: 10.1021/jo801866z

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