Resolution of Enantiomers

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Chapter: Organic Chemistry : Stereochemical and Conformational Isomerism

We have seen that individual enantiomers have identical physical properties and only can be distinguished in a chiral environment. Plane-polarized light is such a chiral environment, and one enantiomer is dextrorotatory and one is levorotatory.


We have seen that individual enantiomers have identical physical properties and only can be distinguished in a chiral environment. Plane-polarized light is such a chiral environment, and one enantiomer is dextrorotatory and one is levorotatory. Another way to distinguish enantiomers is to allow them to react (or interact) with other chiral molecules. The interaction of a mixture of enantiomers with a single enantiomer of a chiral molecule produces a mixture of diastereomers as illustrated.

Since diastereomers have different physical properties, they can be separated on the basis of those physical properties. After separation of the diastereomers, the individual enantiomers are reclaimed, and in this way the two enantiomers will have been separated. Such interactions form the basis for all separations of racemic mixtures into pure enantiomers, which is termed “resolution” of enan-tiomers. There are several experimental techniques used to resolve enantiomers, but all utilize a chiral reagent of some type to furnish the chiral environment needed to distinguish the enantiomers.

Crystallization has been a traditional method for separating the diastereomers produced from a racemic mixture and a chiral resolving agent. For example, racemic carboxylic acids can be treated with an optically active alkaloid (which is basic) and the resulting diastereomeric salts are separated by crystallization. The individual enantiomeric acids are then regenerated from the salts. A vari-ety of alkaloids have been used as resolving agents for racemic acids. They include brucine strychnine, ephedrine, quinine, morphine, and α-phenyl ethy-lamine, among others.

Racemic bases can be resolved by treating them with an optically active acid and separating the resulting diastereomeric salts by fractional crystalliza-tion. The individual enantiomeric bases are regenerated from the salts. Common acid-resolving agents include camphorsulfonic acid and derivatives of it, tartaric acid, malic acid, and pyroglutamic acid, among others.

Alcohols are often resolved by conversion to half esters of phthalic acid or succinic acid, which are then resolved as typical acids. The alcohol is then regen-erated from the resolved half ester by hydrolysis or reductive cleavage with LAH. A second method for resolving alcohols is to convert them to esters of optically active acids. This gives a mixture of diastereomeric esters which are separated by fractional crystallization and the alcohol is recovered by hydrolysis or reductive cleavage.

In recent times chromatography has become a major technique for separations and has increasingly supplanted fractional crystallization as a way to separate diastereomeric compounds. Not only do diastereomers have different solubilities, they also interact with surfaces such as silica gel or alumina differently. The mix-ture of diastereomeric esters obtained by coupling a racemic alcohol to optically active acid can often be separated by high-performance liquid chromatography (HPLC), radial chromatography, or flash chromatography. Chromatography is often much faster and more efficient than crystallization. The individual alcohols can be regenerated in the usual fashion.

The preceding methods for the resolution of enantiomers rely on the forma-tion of strongly bound diastereomers (ionic or covalent) which are then sep-arated. It has become more and more common to use weak interactions as a means of resolving enantiomers. Chiral chromatography columns are useful for the separation of a variety of compounds, including amino acids. A chi-ral substance is permanently attached to the column surface. If a mixture of enantiomers is passed over the surface, the individual enantiomers will interact with the chiral surface differently and thus will elute along the column at dif-ferent rates. (The enantiomer which interacts with the surface more strongly will elute more slowly). They can thus be collected individually. A variety of chiral stationary phases are available to separate an ever increasing number of examples.

The use of enzymes to resolve enantiomers has become an extremely popular method only recently. Enzymes are chiral catalysts which often exhibit very high selectivity for one enantiomer of a racemic mixture. Since enzymes are soluble in aqueous solution, it was often impossible to get sufficiently high concentrations of organic substrates in the aqueous medium to achieve conversion at any reasonable rate. The finding that a variety of esterases (lipases) can function very well in organic solvents has removed this major stumbling block to the practical utilization of biochemical transformations for resolution. In addition, a variety of enzymes are available commercially. Moreover a variety of other enzymes are now available and can be used to resolve enantiomers effectively. For example, some amidases and peptidases (amide bond hydrolysis) can be applied to the resolution of enantiomers.

Thus it is very easy to acetylate a racemic alcohol and treat the racemic mixture of acetates with a lipase. One enantiomer is hydrolyzed to the alcohol and the other remains as the ester. These are separated chromatographically and each component is obtained with high optical purity. This technique is becoming more important and could be the most general technique for resolution in the future.

The use of kinetic resolution to obtain a single enantiomer from a mixture of enantiomers is often useful for particular functional groups. Since individual enantiomers react at different rates with chiral reagents, treatment of a racemic mixture with a limited amount (0.5 equiv.) of a chiral reagent will convert one of the enantiomers to product in preference to the other. After workup one enan-tiomer will be recovered unchanged while the other will have been converted to a new product. The efficiency of the kinetic resolution will depend on the relative rates of reaction of the two enantiomers. If rates of reaction (selectivity factor) vary by >100, then the recovered enantiomer will be >99% optically pure. Lower selectivity factors will lead to less pure enantiomers.

Optically active diisopinocamphenylborane can be used to resolve racemic olefins. The reagent adds to one enantiomer, and the other is unchanged. Opti-cal purities on the order of 37 – 65% are possible. Chiral allylic alcohols can be resolved with chiral epoxidizing agents derived from tartrate complexes of titanium. One enantiomer is epoxidized and the other is not. Thus, the two alco-hol enantiomers can be separated, one as the unsaturated alcohol and one as the epoxy alcohol. Use of the other tartrate isomer reverses the stereoselectiv-ity. Selectivities on the order of >100 are possible with this method. As in any kinetic resolution, however, only one enantiomer can be recovered. The other is converted to a different chiral product.

Even if the separation of enantiomers by any of the above methods is not completely successful, it is often possible to further raise the enantiomeric excess by crystallization or chromatography. In this way many pure enantiomers are now available.

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