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Total Synthesis and Biological Evaluation of Amphidinolide V and Analogues
Author(s) -
Fürstner Alois,
Flügge Susanne,
Larionov Oleg,
Takahashi Yohei,
Kubota Takaaki,
Kobayashi Jun'ichi
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802068
Subject(s) - chemistry , enyne metathesis , stereochemistry , metathesis , total synthesis , natural product , diastereomer , salt metathesis reaction , alkyne , ring closing metathesis , organic chemistry , catalysis , polymerization , polymer
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 8 R ,9 S ,10 S ,13 R . 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.