Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 15, Issue 16, Pages 4011-4029Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200802068
Keywords
anticancer agents; macrolides; metathesis; natural products; structure elucidation
Categories
Funding
- MPG
- Chemical Genomics Center
- Fonds der Chemischen Industrie
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A sequence of ring-closing alkyne metathesis followed by an intermolecular enyne metathesis of the resulting cycloalkyne with ethene was used to forge the macrocyclic skeleton and to set the vicinal exo-methylene branches characteristic for the cytotoxic marine natural product amphidinolide V (1). Comparison of the synthetic material with all authentic sample of this extremely scarce metabolite isolated from a dinoflagellate of the Amphidinium sp. eliminated any, doubts about its structure and allowed the absolute configuration of amphidinolide V to be determined as 8R,9S,10S,13R. Moreover, the flexibility inherent to the underlying Synthesis blueprint also opened access to a comprehensive set of diastereomers of I as well as to synthetic analogues differing from the natural lead in the lipophilic chains appended to the macrocyclic core. This set of designed analogues gave first insights into structure-activity relationships, which revealed that the stereo-structure Of the macrolactone is a highly critical parameter, whereas the examined alterations of the side chain did not diminish the cytotoxicity, of the compounds to any notable extent.
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