How can we prepare a chiral compound? PART I

In past blog entries I have shown that chirality is an important property of molecules. In molecules intended to be used as drugs, chirality may be extremely important since the biological effect directly depending on the stereochemistry of the compound (e.g. the thalidomide).
The administration of enantiopure drugs brings benefits in terms of improved efficacy, and reduced toxicity. Consequently, it is not strange that 7 out of the top 10 most selling-drugs worldwide in 2010 are commercialized as enantiopure forms. Therefore, it is relevant to have synthetic methods to access these chiral compounds obtaining just only the enantiomer we are interested in.

Let’s "cook" chiral molecules!

The synthesis of chiral compounds is addressed by an area of chemistry called enantioselective synthesis. Simply: it is the synthesis of a compound by a method that favours the formation of a specific enantiomer. Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals. It has also a prominent role in the food, agrochemical, and perfumery industries.

On the other hand, we must recognize that the social demands on the current chemistry are increasingly higher. Selectivity should be applied to every single stage of chemical production. It is useless to produce the enantiomer with no biological effect (and/or toxic effects). In fact, it is considered waste, so it is worth focusing on obtaining the useful enantiomer only. Chemical waste is not a trivial issue considering that usually chemical synthesis is scaled-up (e.g. production of pharmaceuticals or agrochemicals) and this may be very costly in industrial processes where the economic aspects are crucial.

Chirality cannot be created in molecules by a random chemical process. When a random chemical reaction is used to prepare molecules having chirality, there is an equal opportunity to prepare the left-handed isomer as well as the right-handed isomer. In addition, and more relevant, the preferential formation in a chemical reaction of one enantiomer over the other is result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Chemical synthesis of a chiral molecule from simpler non-chiral precursors usually produces equal amounts of both enantiomers. For this reason, we strictly need a source of chirality.

The three main approaches to access chiral compounds are:

Chiral (or optical) resolution of racemic mixtures:

Namely, physical separation of the pair of enantiomers contained in a 50/50 mixture. This involves the isolation of one enantiomer from the racemic mixture by any of a number of methods. Where the cost in time and money of making such racemic mixtures is low, or if both enantiomers may find use, this approach may remain cost-effective.

Synthetic transformations from an enantiomerically pure starting compound:

In the particular case of using an easily available natural compound as starting material it is called chiral pool synthesis. This methodology is more useful when the desired final product and the chiral compound used are structurally similar. Carbohydrates, amino acids, hydroxy acids and terpenes integrate the chiral pool arsenal.

Stereoselective synthesis:

This approach involves the use of a prochiral substrate and an enantiopure reagent as a source of chirality, in stoichiometric (auxiliary) or substoichiometric (catalytic) amounts, which is not included in the final product.

In the next blog entries we are going to have a close look to these three different approaches to have access to chiral compounds highlighting pros and cons of each method.