Category Archives: D Medicines and Drugs

Chirality in Drugs

Many drugs are optically active compounds.  Often it is only one enantiomer that has the desired therapeutic effect.  Thalidomide, a drug used to treat morning sickness in pregnant women in the 1960s is an example of this.

The two enantiomers of Thalidomide

The R isomer (pictured on the right above) acts as a sedative while the S isomer (pictured on the left) has teratogenic properties that resulted in thousands of children being born with deformities.

Thalidomide was produced and sold as a racemic mixture of the two enantiomers which resulted in the birth defects.  Even if it was produced in a pure enantiomeric form, this wouldn’t have solved the problem as there is evidence that the enantiomers can convert under physiological conditions.  Mass producing pure enantiomeric forms of drugs can be expensive and low yielding.

Taxol is another drug that has a complex level of chirality.  In total, Taxol has 11 asymmetric carbon atoms.  Taxol is used to treat cancer and is a naturally occurring substance that is found in the bark of Yew trees.

The structure of Taxol

Obtaining Taxol from its natural source is extremely low yielding and causes environmental damage as it destroys the trees.  Synthesising the drug from scratch in the laboratory would require a large multistep process that would also prove low yielding and extremely costly.

As such, a compromise is found and the drug is produced by a semi-synthetic route starting with a material found in the needles of the Yew tree.

This is a more advantageous method as harvesting the needles of the tree does not cause as much environmental damage and significantly lessens the number of steps needed to manufacture the final product.  In addition, the overall yield of Taxol is improved compared to extraction from the bark.

The challenge in the synthesis is creating the correctly oriented chiral centres.  This is done through a method known as asymmetric synthesis.

 

Asymmetric synthesis involves using a chiral auxiliary attached to the molecule to force through steric hindrance the predominance of one enantiomer over another.

Consider the achiral molecule below.  It is possible to make two enantiomers by adding an amino group to carbon 2.

If you want to favour the production of one enantiomer over the other, attaching a chiral auxiliary molecule to force the addition of the amino group by blocking the path of attack from one side of the molecule.  Below is an example of one such chiral auxiliary.

Notice how the addition of the chiral auxiliary hinders attack from one side of the molecule.  This doesn’t eliminate the production of the unwanted enantiomer but greatly decreases it.

Once the reaction is complete, the chiral auxiliary can be removed for reuse and the final product isolated.