Macrolactamization versus Macrolactonization: Total Synthesis of FK228, the Depsipeptide Histone Deacetylase Inhibitor
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 analogu...
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| Veröffentlicht in: | Journal of organic chemistry 2008-12, Vol.73 (23), p.9353-9361 |
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| container_end_page | 9361 |
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| container_issue | 23 |
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| container_title | Journal of organic chemistry |
| container_volume | 73 |
| creator | Wen, Shijun Packham, Graham Ganesan, A |
| description | 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. |
| doi_str_mv | 10.1021/jo801866z |
| format | Article |
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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. 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Org. Chem</addtitle><description>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. 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Org. Chem</addtitle><date>2008-12-05</date><risdate>2008</risdate><volume>73</volume><issue>23</issue><spage>9353</spage><epage>9361</epage><pages>9353-9361</pages><issn>0022-3263</issn><eissn>1520-6904</eissn><coden>JOCEAH</coden><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. 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| ispartof | Journal of organic chemistry, 2008-12, Vol.73 (23), p.9353-9361 |
| issn | 0022-3263 1520-6904 |
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| subjects | Alcohols - chemistry Antibiotics, Antineoplastic - chemical synthesis Antibiotics, Antineoplastic - chemistry Carboxylic Acids - chemistry Chemistry Chemistry, Organic - methods Chemistry, Pharmaceutical - methods Depsipeptides - chemical synthesis Depsipeptides - chemistry Drug Design Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives Heterocyclic compounds with only one n hetero atom and condensed derivatives Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Lactones - chemistry Models, Chemical Organic chemistry Peptides Peptides - chemistry Preparations and properties |
| title | Macrolactamization versus Macrolactonization: Total Synthesis of FK228, the Depsipeptide Histone Deacetylase Inhibitor |
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