Enantiomers preferential crystallization

Enantiomers, preferential crystallization of 59 Endo selectivity 798 Ene reactions 808, 809 Enones, synthesis of 732 Enthalpies of formation 102, 103 Enynes, synthesis of 956 Enzymatic kinetic resolution 829 Epimerization 399 Episulphides, oxidation of 237 Episulphones 650, 775 Episulphoxides, photolysis of 742 a,/J-Epoxysulphones reactions of 811, 812 rearrangement of 685 synthesis of 612 / ,y-Epoxysulphones 781 y,<5-Epoxysulphones 627, 628 Epoxysulphoxides reactions of 613 rearrangement of 744 synthesis of 327, 612 Erythronolides 831... 

In the optical resolution of DL-threonine mixtures by batch preferential crystallization, changes of solution concentration and crystal purity were measured. The mechanism of nucleation of the un-seeded enantiomer was discussed to explain the purity decrease of the resolved crystals. From the observation of crystallization behavior of the seed crystals of L-threonine, it was concluded that the existence of the D-enantiomer on the surface of the seed caused the sudden nucleation when they grew to attain sufficient amounts. 

The diamine (99) was prepared from (S)-proline90b) or (S)-glutamic acid I15) maintaining the asymmetric center. Racemic 2-(anilinomethyl)pyrrolidine, prepared from (RS)-5-oxopyrrolidine-2-carboxylic acid, was effectively resolved into a pair of enantiomers by fractional crystallization of its mandelic acid salt U6). Moreover, the preferential crystallization of its 4-hydrobenzoic acid salt was found to produce both enantiomers in high optical purities by alternate seeding116). 

The separation of a racemic compound into its enantiomers is called resolution. Various methodologies have been used for the resolution of the enantiomers on both analytical and preparative scales. The different techniques may be categorized into two classes the classical approach, using enzymatic degradation of one of the enantiomers, and preferential crystallization. Modem technologies include spectroscopic, electrophoretic, and chromatographic methods. 

It is worth to mention that both coordination compounds, namely [Ca(7)2]DBTA and [Ca(H20)](12)DBTA form conglomerates with their enantiomers, respectively. Thus, optical resolution of racemic DBTA by preferential crystallization of these coordination complexes is also possible. [26, 27]... 

Figure 1. A racemic conglomerate (a) the principle of Preferential Crystallization, (b) a packing mode of enantiomers in the crystal with Z = 2, and (c) a representative binary melting-point phase diagram.

A more useful variation of the mechanical separation applied by Pasteur is the method of inoculation, originally discovered by Gemez in 1866.7 This is a method in which a supersaturated solution of a racemic mixture is inoculated with pure crystals of one of the enantiomers and let only the crystals of the same kind of enantiomer are allowed to grow selectively. This method is called preferential crystallization or entrainment. 

In this process, the readily soluble co-existing salt is in equilibrium with the target salts, and acts as a buffer to the supersaturation of the opposite enantiomer. Thus, we can carry out the preferential crystallization procedure more easily and effectively. For instance, a-methylbenzylamine cinnamic acid salt can be efficiently resolved by adding hydrochloric acid salt of the racemic amine as a co-existing salt. 

In case the racemate is a true racemic mixture, this cannot be separated by preferential crystallization, but can be resolved using the diastereomer crystallization developed by Pasteur in 1848. A solution of the racemic mixture in water or methanol is allowed to react with a pure enantiomer (resolving agent), thereby forming a mixture of diastereomers that can be separated by crystallization. 

Preferential crystallization. Preferential crystallization is one of the oldest methods for the resolution of racemates. It involves seeding of the racemate solution with pure crystals of the desired enantiomer which induce the preferential crystallization of that isomer from the solution. The technology is used in the commercial production of a-methyl-L-dopa (7). 

Resolution by entrainment can sometimes be used to separate racemic mixtures when there are distinct differences in the rates of crystallization of the two optical isomers. This preferential crystallization is initiated by seeding with the crystals of one enantiomer. This technique has been shown to be effective in the production of thiamphenicol (21). 

Preferential crystallization of one enantiomer (occurs for conglomerates, not true racemic crystals)... 

Figure 5.1 shows the procedure for preferential crystallization. Mutual seedings of small amounts of crystals of both enantiomers of a racemate to a supersaturated solution of the racemate alternatively give large amounts of the corresponding enantiomers. Thus, the preferential crystalhzation is very simple and therefore a fascinating way to obtain both enantiomers of a racemate. However, preferential crystalhzation is not always apphed to any racemate. 

As previously indicated, acrylamide 19, irradiated in solution in the presence of a tartric acid derivative, led to an ee < 42% [57]. However, when crystals of a 1 1 complex of 19 with the chiral host 241c were irradiated, an ee of 99% was obtained. Furthermore, a small change in the cavity of the host, as determined by a modification of the ketal bridge from 241c to b, completely reversed the enantiomer preferentially isolated, albeit with a similar ee [189]. A study of the X-ray structures of the complexes should verify whether a change in the helicity of the conformation of the acrylamides 19, 22, and 247 in the complexes was induced by such a modification of the host [181]. 

Crystallization Method. Such methods as mechanical separation, preferential crystallization, and substitution crystallization procedures are included in this category. The preferential crystaUization method is the most popular. The general procedure is to inoculate a saturated solution of the racemic mixture with a seed of the desired enantiomer. Resolutions by this method have been reported for histidine (43), glutamic acid (44), DOPA (45), threonine (46), A/-acetyl phenjialanine (47), and others. In the case of glutamic acid, the method had been used for industrial manufacture (48). 

In addition to the solubility behaviour, the selection of solvents is also important since solvents can change the solubilities of the enantiomers under consideration. Shiraiwa et al. (3) reported that the control of the solvent composition could eliminate the purity drop by the preferential crystallization for the racemic compound forming system of (R -Tyiosinc 4-chlorobenzenesulfonate (Figure 5) in which the solvents examined were mixtures of ethanol and 4-chlorobenzene sulfonic acid (CBA). 

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