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

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

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

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)