Enantiomers enantioseparation

An alternative model has been proposed in which the chiral mobile-phase additive is thought to modify the conventional, achiral stationary phase in situ thus, dynamically generating a chiral stationary phase. In this case, the enantioseparation is governed by the differences in the association between the enantiomers and the chiral selector in the stationary phase. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Enantioseparation is typically achieved as a result of the differences in interaction energies A(AG) between each enantiomer and a selector. This difference does not need to be very large, a modest A(AG) = 0.24 kcal/mol is sufficient to achieve a separation factor a of 1.5. Another mechanism of discrimination of enantiomers involves the preferential inclusion of one into a cavity or within the helical structure of a polymer. The selectivity of a selector is most often expressed in terms of retention of both enantiomers using the separation factor a that is defined as ... 

Discrimination between the enantiomers of a racemic mixture is a complex task in analytical sciences. Because enantiomers differ only in their structural orientation, and not in their physico-chemical properties, separation can only be achieved within an environment which is unichiral. Unichiral means that a counterpart of the race-mate to be separated consists of a pure enantiomeric form, or shows at least enrichment in one isomeric form. Discrimination or separation can be performed by a wide variety of adsorption techniques, e.g. chromatography in different modes and electrophoresis. As explained above, the enantioseparation of a racemate requires a non-racemic counterpart, and this can be presented in three different ways ... 

Other examples of enantioseparations include the separation of the antihelmintic drug, prazinquatel [35], which used a 4-column SMB system composed of columns of 12.5 mm i.d. packed with CTA and with methanol as the eluent. Ikeda and Murata separated the enantiomers of (3-blockers [36]. 

Efficient methods of enantioseparation are always required to control the enantiomeric purity, or to separate the target molecule or one of its chemical precursors (obtained from conventional synthetic procedures), or for monitoring the completion of enantioselective reaction process (since the production of single enantiomer is a real difficult task). 

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

Keywords enantioseparation, racemic mixtures, single enantiomer of drug, chromatography, chromatographic resolution. 

For aromatic amino and hydrazino acids and several other structurally related compounds, the influence of MeOH content in both RP and POM was investigated on a teicoplanin CSP [90]. Using a hydroorganic mobile phase, complete enantiosep-arations of a-methylamino acids were not attained. However, this type of separation was suitable for the enantiomers of dopa. Further experiments performed by the same authors in POM allowed the complete enantioseparation of a-methyl-ooPA enantiomers [91]. 

Later, a commercially available TAG CSP was tested in the enantioseparation of 10 secondary a-amino acids, by using RP mobile mode systems [154]. The chromatographic results, compared with those obtained on a native teicoplanin CSP, were given as the retention, separation, and resolution factors, together with the enanti-oselective free energy difference corresponding to the separation of the investigated enantiomers. 

Rojkovieova, T. et al.. Study of the mechanism of enantioseparation. Vll. Effect of temperature on retention of some enantiomers of phenylcarbamic acid derivates on a teicoplanin aglycone chiral stationary phase, J. Liq. Chrom. Rel. TechnoL, 27, 1653, 2004. 

More than 100 CSPs are commercially available nowadays, which should make the separation of any pair of enantiomers feasible. However, the enantiorecognition mechanisms involved in the chiral recognition between the analytes and the CSPs are complex and therefore the selection of the appropriate CSPs, depending on the structure of the analyte, is a difficult task. A common approach to develop a new enantioseparation is the stepwise trial-and-error approach based on detailed consideration of the enantiorecognition mechanisms between the chiral selector and the analyte, or on the analyst s experience, or on the consultation of literature or databases. However, this approach is time-consuming and often unsuccessful owing to the fact that achieving enantioresolution is often purely empirical... 

From the method development and robustness point of view, the temperature is a parameter that controls equilibria such as pK and enantiomer—chiral selector complexation, or induces structural changes in, e.g., proteins.For chiral separations, generally a lower temperature results in better enantioseparation, but even the opposite has been observed. Sometimes a raise in temperature does not so much affect the enantiomeric separation, but increases the resolution between an enantiomer and a matrix component. ... 

The existence of the aforementioned difference between the mobilities of transient diastereomeric complexes of the enantiomers with the chiral selector may have some important consequences in chiral CE. For instance, the enantioseparation can, in principle, be possible even in those cases when the binding constants of both enantiomers to a given chiral selector are the same. On the other hand, this may allow, in certain cases, observation of the reversal of the enantiomer migration order, depending on the concentration of the chiral selector (17). 

Cooper et al. (26) determined the binding constants and the mobility characteristics for three binaphthyl derivatives with a-, / -, and y-CDs. As shown, the transient diastereomeric complexes of the enantiomers of these compounds differ from each other in their mobilities. This effect is most pronounced in the case of l,l -binaphthalene-2,2 -diyl hydrogen phosphate. The change in enantioseparation depending on the y-CD concentration could be explained well for each solute-y-CD pair based on the binding studies. 

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