Total Synthesis of the Antimitotic Marine Macrolide (−)-Leiodermatolide

Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin‐targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2014-03, Vol.53 (10), p.2692-2695
Main Authors: Paterson, Ian, Ng, Kenneth K.-H., Williams, Simon, Millican, David C., Dalby, Stephen M.
Format: Article
Language:English
Subjects:
aldol reaction
Animals
Antimitotic Agents - chemical synthesis
Antimitotic Agents - chemistry
antitumor agents
Communications
cross-coupling
macrolides
Macrolides - chemical synthesis
Macrolides - chemistry
Molecular Conformation
Pharmaceutical industry
Porifera - chemistry
Stereoisomerism
total synthesis
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Summary:Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin‐targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2 % yield) based on a convergent sequence of palladium‐mediated fragment assembly and macrolactonization. Boron‐mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate‐derived ketone 7. Supply to meet the demand: The tubulin‐targeting mechanism of action of the marine macrolide leiodermatolide makes it a novel lead for anticancer drug discovery. With the aim of ensuring a sustainable supply and enabling structure–activity‐relationship studies, a convergent synthetic route based on palladium‐mediated fragment assembly and macrolactonization was developed (see scheme). Boron‐mediated aldol reactions set six of the nine stereocenters.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201310164