How can we prepare a chiral compound? PART III. Chiral pool synthesis.

In the previous post (see post How can we prepare a chiral compound? PART II, 31 Dec 2014) I have shown that one of the main approaches to access chiral compounds is the chiral resolution of racemic mixtures.

Another alternative available for obtaining chiral compound is carrying out synthetic transformations from an enantiomerically pure starting compound. In the specific case of using simply available natural compounds as starting materials, it is called chiral pool synthesis. This method is particularly interesting when the desired final product and the chiral compound used as starting material are structurally similar, i.e. the chiral natural product as starting material is wholly or partially built into the target molecule.
The main compounds from the chiral pool that have been used for this purpose are α-amino acids, hydroxyacids, carbohydrates and terpenes. These natural compounds have some advantageous properties: their optical purity is normally close to 100% they are in general non-toxic and many are inexpensive starting materials.

However, this strategy may not be especially helpful if the desired molecule does not bear a great resemblance to inexpensive enantiopure natural products. Otherwise, a long, probably difficult synthesis involving many steps may be required. In addition, it may be challenging to find a suitable enantiopure starting material, so other approaches may prove more fruitful.

Organic chemistry is like playing with Lego®

There is a high demand for ready access to chiral drugs in the pharma industry and chiral pool synthesis has been used for this purpose in some of the current well-known drugs.
Organic chemistry bring us the possibility to mimic Nature in order to have access to these natural compounds (with therapeutic properties) or modified and improved efficacy compounds. Easily and giving an example linked to our daily lives, organic synthesis resembles playing Lego®. Organic chemists have a huge toolbox filled with small Lego® bricks (our building blocks). Smart combination and assembly of these Lego® bricks let us to build up more complex structures (our targeted drug). In particular, the chiral pool synthesis rummages in Nature to find these tiny chiral blocks that fit the complex structure we want to build up by means of chemical reactions.

Chiral pool synthesis is a strategy that aims to improve the efficiency of organic synthesis. It starts the synthesis of a complex enantiopure chemical compound from a stock of readily available enantiopure substances. Let me have a look to two examples of chiral pool synthesis to illustrate the usefulness of this methodology. 

The drug Imipenem is a beta-lactam antibiotic for intravenous use administered in hospitals for the treatment of several bacterial infections. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic healthcare system. It was discovered by Merck scientists when searching for a more stable version of the natural product thienamycin, which is produced by bacterium.

The pharma company Merck markets the drug Imipenem (in combination with cilastatin to enhance its therapeutic effect) under the trade names Primaxin® or Tienam®. The synthesis of Imipenem is carried out by using aspartic acid as starting material. Aspartic acid is one of the 20 existing natural aminoacids present in Nature (our chiral pool) commonly used in chiral pool synthesis due to its ready availability, low cost and simple structure. From aspartic acid through several chemical reactions the structure of Imipenem is built up (highlighted in red the fragment coming from the starting material incorporated into the final molecule).

The drug Oseltamivir is marketed under the trade name Tamiflu® by the pharma company Hoffmann-La Roche. It is an antiviral medication used to prevent and treat influenza A and influenza B (flu). It is also on the World Health Organization's List of Essential Medicines. Its commercial production starts from the molecule shikimic acid harvested from Chinese star anise (Illicium verum) with a limited worldwide supply (highlighted in red the fragment coming from the starting material incorporated into the final molecule).

Due to the limited supply of shikimic acid, searches for alternative synthetic routes preferably not requiring shikimic acid are underway and to date several other alternatives routes have been proposed.
Both examples, Imipenem and Oseltamivir, show us how we can take advantatge of the chiral pool for obtaining chiral drugs very useful for treating diseases.