Formal Total Synthesis of (–)-Taxol

  • Author: Claire D'Andola
  • Published Date: 31 October 2014
  • Source / Publisher: Chemistry – A European Journal/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
thumbnail image: Formal Total Synthesis of (–)-Taxol

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Taxol, isolated from the bark of the Pacific yew tree (Taxus brevifolia), displays potent bioactivity and has been widely used as an anticancer drug. The complex structure of taxol, which includes a highly distorted 6-8-6 taxane scaffold with nine stereogenic centers (including an all-carbon quaternary stereogenic center), diverse functional groups such as oxetane, trans-1,2-diol, acyloin, and a bridgehead double bond, combined with its biological properties has made it an attractive and challenging synthetic target.


The formation of the eight-membered carbocyclic ring, in particular, has been a significant problem in some previous syntheses because of its highly strained nature arising from transannular strain.


Masahisa Nakada and colleagues, Waseda University, Japan, have tackled these challenges by envisioning a convergent total synthesis of (–)-taxol. They prepare the initial building blocks of (–)-taxol in a parallel fashion, thus reducing time and also providing the advantage of the independent transformations of functional groups that are otherwise incompatible with each other. The problem of forming the eight-membered carbocyclic ring was then solved by using the palladium-catalyzed intramolecular alkenylation of a methyl ketone, thus affording the cyclized product in an excellent yield (96 %).

 

 

The nature of this convergent approach has the potential to enable the synthesis of diverse taxol derivatives and work is currently underway to reduce the number of synthetic steps.


 

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