Total synthesis and biological evaluation of amphidinolide V and analogues

The awesome power of metathesis is illustrated by a concise synthesis of the extremely scarce marine natural product amphidinolide V, which hinges on a sequence of ring-closing alkyne metathesis followed by intermolecular enyne metathesis with ethylene (see scheme). As a complete set of conceivable stereoisomers was prepared, the constitution and absolute configuration of this macrolide could be established and first insights into structure-activity relationships governing its cytotoxicity were obtained.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 an 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 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 stereostructure 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.