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Enantioselective Total Synthesis of (+)-Largazole, a Potent Inhibitor of Histone Deacetylase†
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Dedicated to Professor E. J. Corey with profound admiration and appreciation on the occasion of his 80th birthday.
Section:Abstract
An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (1) 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 4 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.
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This article has been cited by 16 ACS Journal articles (5 most recent appear below).
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Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation
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Robert M. WilliamsThe Journal of Organic Chemistry2011 Article ASAPNatural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism
Robert M. WilliamsThe Journal of Organic Chemistry2011 Article ASAPSelected examples from our laboratory of how synthetic technology platforms developed for the total synthesis of several disparate families of natural products was harnessed to penetrate biomechanistic and/or biosynthetic queries is discussed. Unexpected ...
In Vitro and In Vivo Osteogenic Activity of Largazole
Su-Ui Lee, Han Bok Kwak, Sung-Hee Pi, Hyung-Keun You, Seong Rim Byeon, Yongcheng Ying, Hendrik Luesch, Jiyong Hong, and Seong Hwan KimACS Medicinal Chemistry Letters2011 2 (3), 248-251In Vitro and In Vivo Osteogenic Activity of Largazole
Su-Ui Lee, Han Bok Kwak, Sung-Hee Pi, Hyung-Keun You, Seong Rim Byeon, Yongcheng Ying, Hendrik Luesch, Jiyong Hong, and Seong Hwan KimACS Medicinal Chemistry Letters2011 2 (3), 248-251Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone ...
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History
- Published In Issue September 04, 2008
- Article ASAPJuly 29, 2008
- Received: June 27, 2008
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