Total synthesis and biological evaluation of amphidinolide v and analogues

Alois Fürstner, Susanne Flügge, Oleg Larionov, Yohei Takahashi, Takaaki Kubota, Juńichi Kobayashi

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

A sequence of ring-closing alkyne metathesis followed by an inter-molecular enyne metathesis of the resulting cyeloalkyne with ethene was used to forge the macrocyclic skeleton and to set the vicinal exo-methylene branches characteristic for the cytotox-ic marine natural product amphidino-lide V (1). Comparison of the synthetic material with an authentic sample of this extremely scarce metabolite isolated from a dinoflagellate of the Amphi- dinium 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 1 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.

Original languageEnglish
Pages (from-to)4011-4029
Number of pages19
JournalChemistry - A European Journal
Volume15
Issue number16
DOIs
Publication statusPublished - Apr 14 2009
Externally publishedYes

Keywords

  • Anticancer agents
  • Macrolides
  • Metathesis
  • Natural products
  • Structure elucidation

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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