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Synthesis 2009(17): 2873-2880  
DOI: 10.1055/s-0029-1216931
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of Largazole - Devolution of a Novel Synthetic Strategy

Bo Wang, Craig J. Forsyth*
Department of Chemistry, The Ohio State University, 100 W 18th Ave, Columbus, OH 43210, USA
Fax: +1(614)2921685; e-Mail: forsyth@chemistry.ohio-state.edu;
Further Information

Publication History

Received 25 June 2009
Publication Date:
14 August 2009 (online)

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Abstract

The cyanobacterial isolate largazole embodies a compelling combination of a relatively simple, yet unique cyclic depsipeptide structure with remarkable levels of selective cytotoxicity against cancer cell lines versus nontransformed cells. The unique structure of largazole inspired a strategically novel and aggressive approach towards its expedient total synthesis. This involved an initial dissection into an epoxy aldehyde and an unprotected tetrapeptide, representing the polyketide and polypeptide domains of largazole, respectively. These fragments were successfully joined using NHC-mediated amidation, but subsequent assembly of the cyclic depsipeptide via lactonization was thwarted. A reordering of key couplings led to a successful assembly of largazole.

Key words

total synthesis - heterocycles - depsipeptide - N-heterocyclic carbene - thiazoline

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