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Separation of Enantiomers (Resolution of Racemates)

Obtaining enantiomerically pure medicinal drugs

One obvious way to obtain enantiomerically pure medicinal drugs is to isolate natural products from the chiral pool of nature and, if necessary, to derivatize them. Yet, another possibility is a racemic synthesis and the subsequent separation of the enantiomers (resolution of racemates). However, half of this process's result would be undesired side product. As more and more enantiomerically pure active agents are required today, selective synthesis is the subject of many research projects. The selective synthesis of enantiomers is called asymmetric synthesis, while the corresponding technology is chiral technology.

Separation of enantiomers

Resolution of racemates
The resolution of racemates is the separation of an equimolar mixture of enantiomers (racemate) by physical or chemical methods. Usually, the separation is carried out after a preceding conversion of the enantiomers into diastereomers, because, as a result of their practically identical chemical and physical properties, entantiomers cannot be separated directly. Certainly, the methods of the resolution of racemates can also be applied to non-equimolar mixtures of enantiomers that are usually obtained by asymmetric synthesis, since asymmetric synthesis can never have a stereoselectivity of 100 %.
Methods of resolution of racemates
Manual separation of enantiomers In the crystallization process of enantiomers, derived a racemic mixture, the enantiomers crystallize separately and form two macroscopically different kinds of crystals with a mirror-image relationship. These crystals can be separated manually with a pair of tweezers.
Resolution of racemates after conversion into diastereomers By salt formation with a chiral acid or base, enantiomers can be converted into diastereomers, which can then be separated as a result of their different physical and chemical properties. Subsequently, the acid or base is released and the pure enantiomers are recovered.Covalent derivatization of enantiomers with chiral reagents also yields diastereomers. The diastereomers are separated by common separation techniques, as they possess different physical and chemical properties. Afterwards, separated derivatives are returned to the initial chiral reagent and the desired pure enantiomers.In addition, the separation of enantiomers can be carried out by chromatographic methods, such as gas chromatography (GC), high-pressure liquid chromatography (HPLC), and thin-layer chromatography (TLC) in association with a chiral stationary phase, which retards one enantiomer relatively more than the other one by stereoselectively constructing of diversely stable, chiral complexes.
Biochemical resolution of racemates Most enzymes convert their substrate in an enantioselective way. Therefore, microorganisms can be used to metabolize only one of the enantiomers of a racemate. If the microorganism is wisely chosen, the desired enantiomer is the only thing that remains and can then be separated from the mixture by common separation techniques.
Kinetic resolution of enantiomers In the reaction with chiral reaction partners or chiral catalysts, enantiomers display different reaction rates. If the difference is large enough, the enantiomers can be separated by stereoselectively converting only one of the enantiomers, while the desired enantiomer remains. Since this is based on different reaction rates, the separation technique is called kinetic resolution. A special case of kinetic resolution is the biochemical resolution of racemates by stereoselective enzymic conversion of one enantiomer.

Synthesis of enantiomerically pure compounds

Asymmetric synthesis
Asymmetric synthesis is a reaction or reaction sequence in which one configuration of one or more new stereogenic elements is selectively formed. In an asymmetric synthesis, an achiral molecule is enantioselectively converted into a chiral molecule or a chiral molecule is diastereoselectively converted into a new chiral molecule that contains at least one more chirality element.Summary: In an asymmetric synthesis the enantiomers (or diastereomers) of a chiral product are formed in different yields.

In effect, a synthesis can be stereoselective if it displays a diastereomeric transition state, because the transition states for the formation of the different stereoisomeric products then usually contain different energies. As a result, the activation energies differ from each other. Consequently, the stereoisomer whose formation requires the lower activation energy is preferably formed. The stereoselectivity increases with growing energy difference of the transition states. An unconditional prerequisite for a diastereomeric transition state is the presence of at least one chiral reactant. This may be either the substrate, a reagent, or a catalyst.

Methods of asymmetric synthesis
Stoichiometric methodsDescription
Controlled by reagent In an asymmetric synthesis, if an achiral molecule (substrate) should be stereoselectively converted into a chiral molecule by reaction with an achiral reagent, one of the reactants must previously be made chiral. This is achieved by covalently attaching a chiral molecule to a substrate that can be removed and intactly recovered after the asymmetric synthesis. Such a chiral molecule is called chiral auxiliary. The stereoselectivity of the asymmetric synthesis is then controlled by the stereochemistry of the chiral auxiliary. Certainly, in order to successfuly achieve a diastereomeric transition state, a chiral reagent that will not be recovered after the synthesis can also be applied. The stereochemistry of the chiral auxiliary, or the chiral reagent, respectively, controls the stereoselectivity of the asymmetric synthesis. In contrast to a chiral catalyst, the chiral auxiliary, as well as the chiral reagent, must be applied in appropiate amounts, according to the stoichiometry of the reaction. Therefore, that kind of asymmetric synthesis is a stoichiometric, reagent-controlled method. A well-known example of such an asymmetric synthesis is the hydration of alkenes by the reaction sequence of hydroboration, oxidation, and hydrolysis in association with a chiral borane reagent.
Controlled by substrate If the substrate is chiral, the reagent does not necessarily have to be chiral for an asymmetric synthesis, too. In this case, the stereoselectivity is controlled by the stereochemistry of the substrate. The substrate is obviously applied in stoichiometric amounts. Therefore, the asymmetric synthesis is a stoichiometric, substrate-controlled method.The chiral substrate of such asymmetric syntheses frequently derives from the large pool of chiral natural products. These starting products are often easily available in an enantiomerically (or diastereomerically) pure form and are, therefore, cheaper than chemically synthesized enantiomerically (or diastereomerically) pure starting products. Examples of such chiral natural products are carbohydrates, optically active carbon acids, terpenes, and sesquiterpenes.However, for many asymmetric syntheses, no suitable chiral substrate can be found in the chiral pool of natural products. In such a case, the advantages of reagent- or catalyst-controlled asymmetric syntheses are obvious: they are broadly applicable and contain a high flexibility with respect to the range of starting products and products.

An asymmetric synthesis can also be achieved by applying a chiral catalyst. The catalyst can be an enzyme, or a synthetic catalyst, usually one such as a chiral transition-metal catalyst. Catalytic asymmetric syntheses are usually more cost-effective, though the enzymes and chiral transition-metal catalysts are often more expensive than chiral auxiliaries or reagents, because they have to be applied in small, catalytic quantities instead of stoichiometric amounts. Therefore, an additional advantage of catalytic processes is that the disposal of byproducts poses less of an environmental impact. However, a disadvantage is the toxicity of transition metals.

Methods of asymmetric synthesis
Catalytic methodsDescription
Synthetic catalysts In industrial asymmetric syntheses, more and more transition-metal catalysts with chiral ligands are applied. A well-known example of an asymmetric synthesis used in a large-scale production is the Monsanto process for the manufacture of L-DOPA (L-dihydroxyphenylalanine). This proved useful in the treatment of Parkinson's disease. In one catalytical step of this asymmetric synthesis, a chiral rhodium catalyst is applied to a stereoselective hydrogenation of a double bond.
Enzymes Enzymes show a high enantioselectivity (or diastereoselectivity) in asymmetric syntheses. However, an enzyme can often be applied only to the conversion of a very small group of substrates and, generally, not to a special process. In addition, they usually need physiologic reaction conditions.
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