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

Shijun Wen, Graham Packham, A. Ganesan

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)9353-9361
Number of pages9
JournalThe Journal of Organic Chemistry
Volume73
Issue number23
DOIs
Publication statusPublished - 7 Nov 2008

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