Enantioseparations

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. 

S. Allenmark, Chromatographic Enantioseparations (Methods and Applications), 2nd Edn, Eliss Horwood Publ. New York, 1991. ISBN 0131329782. 

G. Subiamanian, ed., A Practical Approach to Chiral Separations by Liquid Chmmatofpa/ihy, VCH Publishers, Vifeinheim, 1994 S. G. AUatmarit. Chromutographic Enantioseparation Methods and Applications, Ellis Horwood, New Yoik, 1991. 

R.-M. Nicoud, G. Fuchs, P Adam, M. Bailly, E. Kusters, F. D. Antia, R. Reuille and E. Sclimid, Prepar ative scale enantiosepar ation of a cliiral epoxide compar ison of liquid cliromatography and simulated moving bed adsorption technology . Chirality 5 267-271 (1993). 

C. Wolf and W. FI. Prrkle, Enantioseparations by subcritical fluid cliromatography at cryogenic temperatures , 7. Chromatogr. 785 173-178 (1997). 

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. 

S. G. Allenmark, Chromatographic Enantioseparations methods and applications, Chichester, Ellis Horwood (1991) 2 Ed. 

J. Dingenen, Polysaccharide phases in enantioseparations in A practical approach to chiral separations by liquid chromatography, G. Subramanian, VCH, Weinheim (1994) Chapter 6. 

A chiral separation medium is a complex system. Ideally, interactions that lead to enantioseparation are maximized while nonspecific interactions should be completely suppressed. Typically, a medium for chromatographic separations involves the solid support, the selector, and the linker connecting the two, as shown in scheme 3-1. 

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 ... 

Inspired by the separation ability of cyclic selectors such as cyclodextrins and crown ethers, Malouk s group studied the synthesis of chiral cyclophanes and their intercalation by cation exchange into a lamellar solid acid, a-zirconium phosphate aiming at the preparation of separation media based on solid inorganic-organic conjugates for simple single-plate batch enantioseparations [77-80]. 

Table using 3-3. Enantioseparation of l-methylnaphthoyl-A. A -diethylamide and naproxene CSPs 1-11. methyl ester... 

Fig. 3-7. Evaluation of a focused library of 71 DNB-dipeptide CSPs for enantioseparation of the test racemate 8. (Reprinted with permission from ref. [86], Copyright 1999, American Chemical Society.)...

Allenmark, S. Chromatographic Enantioseparations Methods and Applications Ellis Horwood New York, 1991. 

Fig. 4-2. Screen of REGISTER (data registration tool for enantioseparations).

Since this current study is restricted to the best enantioseparations (a > 1.8), it is quite clear that the tree does not accurately reflect the full information contained in CHIRBASE. 

From this perspective, and with a continued lack of models and a better understanding of enantioseparation mechanisms, we can assume that the role of computers in this field will become increasingly determinant. 

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 ... 

Allenmark, S., Chromatographic enantioseparation, Chichester, Ellis Horwood Ltd., 1988 55... 

Nieoud R. M., Euehs G., Adam P, Bailly M., Kusters E., Antia E, Reuille R., Sehmid E. (1993) Preparative Seale Enantioseparation of a Chiral Epoxide Comparison of Liquid Chromatography and Simulated Moving Bed Adsorption Teehnology, Chirality 5 267-271. 

Kusters E., Gerber G., Antia E. D. (1995) Enantioseparation of a Chiral Epoxide by SMB Chromatography using Chiraleel-OD, Chromatographia 40 387-393. 

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]. 

In a different approach, Stalcup and co-workers [25] used sulfated (3-cyclodextrin for the enantioseparation of piperoxan in work directly derived from earlier CE and classical gel results. Their results were obtained using a continuous free flow apparatus developed by R S Technologies, Inc. Processing rates on the order of 4.5 mg h were reported. 

Some of the initial enthusiasm surrounding chiral SFC was tempered by the fact that many of the same separations had already been achieved by LC [29]. Therefore, researchers were reluctant to add SFC to their analytical laboratories. In some instances, SFC does yield separations that can not be achieved on the same CSP in LC [30, 31]. The enantioseparation of primaquine, an antimalarial compound, on a Chiralcel OD CSP is illustrated in Fig. 12-1 [32]. This compound was not resolved on the same CSP in LC [33]. The reverse situation, where a separation obtained in LC may not be observed on the same CSP in SFC, can also occur [34]. These disparities seem to be related to differences in analyte-eluent and eluent-CSP interac-... 

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