This research is supported by a Marie Curie Action

This research is supported by a Marie Curie Action
This research has received funding from the People Programme (Marie Curie Actions) of the EU (FP7/2007-2013) under REA grant agreement nº PIEF-GA-2013-622413

Wednesday, 31 December 2014

How can we prepare a chiral compound? PART II. Resolution of racemates.

As shown in the previous post (see how can we prepare a chiral compound? PART I, 15 Dec 2014) one of the main approaches to access chiral compounds is the so-called chiral (or optical, or classical) resolution of racemic mixtures.
The classical resolution involves the physical separation of the pair of enantiomers contained in a racemic mixture (i.e. a 50/50 mixture of both enantiomers). The isolation of one of the enantiomer from the racemic mixture is achieved by using a physical method (e.g. crystallization) combined with a chemical reaction in some cases.

Obtaining chiral compounds with tweezers!

Louis Pasteur performed the first optical resolution in 1848, and was able to manually separate two kinds of crystals of racemic tartaric acid salts by using magnifying glasses and tweezers. This fact represented the discovery of molecular chirality and the spontaneous resolution. The process consists of crystallizing a supersaturated solution of racemic sodium ammonium tartrate below 28 ºC. Then, he was able to identify the different shapes of the crystals for each enantiomer. In this case, there is no chemical reaction involved in the resolution. In spite of the simplicity of this separation technique, it is limited to conglomerates. In fact, just only 5-10% of all racemates are known to crystallize as mixtures of enantiopure crystals.

Another interesting process is the so-called preferential crystallization (also called resolution by entrainment). Again, Pasteur in 1882 demonstrated that by seeding a supersaturated solution of sodium ammonium tartrate with one of its enantiomers crystallized preferably the same enantiomer he used as a seed.
Again, there is no chemical reaction involved; we just only take advantage of the different solubility of one enantiomer compared to the other. This means that the crystallization rate of one enantiomer is faster than the other one, crystallizing out from the solution. The microscopic nature of the process of crystallization let us identify that in some specific examples enantiomers can self-recognize better than recognize each other yielding the pure enantiomers in the solid state separately.

Crystallization of conglomerates and resolution by entrainment are reliable processes for the obtention of chiral compounds at the pharma industry mainly because they are easy and economical to implement and scale-up. However, the maximum yield for these processes is 50% (we "lose" the enantiomer we are not interested in) . In addition, our chiral compound of interest should crystallize as conglomerate and as stated above this is restricted to ca. 10% of chiral compounds.

Crystallization of diastereomeric salts

Notably, the vast majority of resolutions involve the conversion of a racemate, by treatment with an enantiomer of a chiral substance (the so-called chiral resolving agent), into diastereomeric salts. Diastereoisomers differ from enantiomers that the latter have the same physical properties. The different solubility of diastereoisomers allow the separation of both products and subsequent treatment with an acid or a base give access to both pure enantiomers. Derivatization to diastereoisomers is possible by salt formation between an amine and a carboxylic acid. The method was introduced (again) by Louis Pasteur in 1853 by resolving racemic tartaric acid with optically active (+)-cinchotoxine.

The use of this method circumvents the issue of crystallization as conglomerate, and allows the use of a broad range of chiral resolving agents from the chiral pool. Even chiral synthetic reagents increase the options of finding the most suitable chiral substance to react with our enantiomer of interest. It is considered the most traditional method of resolving racemates, also easily implemented in the chemical industry. However, we still keep the maximum chemical yield for this process up to 50%.

Towards the "perfect" chiral resolution

Apart from the aforementioned classical resolution process based on physical properties like solubility there are other resolution processes that can led to the separation of both enantiomers with yields above the 50%, ideally up to 100%.
As opposed to chiral resolution, kinetic resolution (KR) does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials.
In particular, kinetic resolution relies on the different reaction rate of the enantiomers with a chiral non racemic reagent. In this case, the reaction rates should differ enough to recover the less reactive or non-reactive enantiomer. The maximum chemical yield for this process is 50% for each enantiomer and one of them is chemically modified. Kinetic resolution reactions utilizing purely synthetic reagents and catalysts are less common than the use of enzymes although a number of useful synthetic catalysts have been developed achieving excellent performances.
Again, Louis Pasteur accomplished the first reported kinetic resolution. After reacting aqueous racemic ammonium tartrate with a mold from Penicillium glaucum, he reisolated the remaining tartrate and found it was enantiomerically pure. The chiral microorganisms present in the mold catalyzed the reaction of (R,R)-tartrate selectively, leaving an excess of (S,S)-tartrate.

As you can observe from the methods above the maximum chemical yield for the enantiomer of interest is 50%. In order to avoid this “loss” of material there is a type of kinetic resolution called dynamic kinetic resolution (DKR) where 100% of a racemic compound can be converted into an enantiopure compound. The same principles of KR applies to DKR. In addition, DKR utilizes a chemical reaction to interconvert the (R) and (S) enantiomers throughout the reaction process (this is called epimerization). At this point, the catalyst can selectively react with a single enantiomer, leading to almost 100% chemical yield.

It is necessary to consider the practicality of utilizing resolutions (classical or kinetic ones) for the preparation of enantiopure products. Even for a chiral molecule, which can be attained through other methods, the racemate may be significantly less expensive than the enantiopure material, resulting in heightened cost-effectiveness even with the inherent "loss" of 50% of the material. The main important aspects to evaluate the effectiveness of these methodologies are: 
  • Inexpensive racemate (and chiral catalyst in KR, DKR). 
  • No appropriate enantioselective synthesis available. 
  • Straightforward separation of starting material and the target enantiomer. 
  • Resolution proceeds selectively at low catalyst loadings (i.e. using small amounts of catalyst).
To date, a number of catalysts for kinetic resolution have been developed that satisfy most, if not all of the above criteria, making them highly practical for use in organic synthesis of chiral compounds.

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