D.7 (HL) Taxol – a chiral auxiliary case study

Taxol

  • Paclitaxel (Taxol) is a drug used to treat several different forms of cancer
  • Discovery
    • In 1960, the American National Cancer Institute (NCI) conducted analysis of several plant materials
    • Pacific yew tree bark showed good activity against certain kind of cancer
    • The obtained material was then fractioned using multi-step portioning and then a pure extract of Taxol was obtained. The yield was 0.004%. The structure of Taxol was determined four years later using X-Ray crystallography
    • Further development was hindered by high costs, low yield, and limited supply of Pacific yew bark
    • Also, it is insoluble, so hard for intravenous injection (into skin)
    • Has 11 chiral carbons so extremely difficult to replicate
  • Taxol destroys cancerous cells by binding to certain proteins and interfering with the process of cell division

Semi-synthetic production

  • Clinical trials of the drug took place (D.1) and the low solubility problem of Taxol was solved
  • For intravenous, a mixture of the drug with chemically modified castor oil and ethanol was diluted with normal saline solution immediately before injection
  • The semi-synthetic method of production taxol used 10-deacetylbaccatin (precursor of taxol) which comes from leaves of European tree and converted to taxol by several synthetic steps including condensation reactions

Chiral auxiliaries

  • To produce Taxol from precursors, the side chains need to be synthesized in laboratories
  • Since the chains contain chiral carbons, it’s hard to make them from non-chiral materials (it would lead to many different stereoisomers). Side chains are synthesized using chiral auxiliaries
  • Chiral auxiliaries: an optically active substance that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of a single enantiomer.
  • Chiral auxiliary used in synthesis of Taxol is trans-2-phenylcyclohexanol
  • Although chiral auxiliaries controls the isomer created, others are created as well. Unwanted isomers can be removed by crystallization, extraction or chromatography
  • Identity and purity of chiral compounds can be determined using a polarimeter
  • Solutions of equal concentrations of isomers are called racemic mixtures and are optically inactive (refer to 20.3 for more info on polarimetry)

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