Scalable enantioselective total synthesis of taxanes

Nat Chem. 2011 Nov 6;4(1):21-5. doi: 10.1038/nchem.1196.

Abstract

Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane--taxadiene--which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Molecular Structure
  • Stereoisomerism
  • Taxoids / chemical synthesis*
  • Taxoids / chemistry

Substances

  • Alkenes
  • Antineoplastic Agents, Phytogenic
  • Diterpenes
  • Taxoids
  • taxa-4(5),11(12)diene

Associated data

  • PubChem-Substance/125317165
  • PubChem-Substance/125317166
  • PubChem-Substance/125317167
  • PubChem-Substance/125317168
  • PubChem-Substance/125317169
  • PubChem-Substance/125317170
  • PubChem-Substance/125317171
  • PubChem-Substance/125317172
  • PubChem-Substance/125317173
  • PubChem-Substance/125317174
  • PubChem-Substance/125317175
  • PubChem-Substance/125317176
  • PubChem-Substance/125317177
  • PubChem-Substance/125317178
  • PubChem-Substance/125317179
  • PubChem-Substance/125317180
  • PubChem-Substance/125317181
  • PubChem-Substance/125317182
  • PubChem-Substance/125317183
  • PubChem-Substance/125317184
  • PubChem-Substance/125317185