Crown enantioseparation

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. 

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]. 

Synergistic effects in terms of efficiency of CE enantioseparation have been observed when a second (not necessarily chiral) selector is added in the same buffer system. It has been demonstrated that a combination of 18-crown-6 and )-cyclodextrin can achieve or enhance enantioselective separations of nonpolar amines, which are rarely observed with cyclodextrins alone <1997JCH(781)129, 1997JCH(695)157>. The formation of a ternary sandwich complex (dual complex) is postulated to be responsible for such a beneficial effect. 

ENANTIOSEPARATION OF PHARMACEUTICALLY RELEVANT CHIRAL COMPOUNDS USING CYCLODEXTRIN, MACROCYCLIC ANTIBIOTIC. AND CROWN-ETHER TYPE CSPs... 

A new crown-ether type CSP, based on (- -)-(18-crown-6)-2,3,l 1,12-tetracarboxylic acid (see Fig. 9.23b), has recently been developed [290- 2]. The use of this type of chiral crown-ether as a selector for LC enantioseparation has been triggered by its previous success in capillary electrophoretic enantioseparations [293,294]. 

For a quite long period of time, chiral ligand-exchange chromatography (CLEC) has been the standard method for the enantioseparation of free amino acids. Meanwhile, other methods became available for these target molecules, such as teicoplanin or chiral crown-ether-based CSPs. However, for the enantioseparation of aliphatic a-hydroxy carboxylic acids, it is still one of the most efficient methods. 

Enantiomeric separations on micromachined electrophoretic devices (MED) have been reported and about 10 research papers [76-87] and one review paper [88] summarize the developments in this field. In all enantioseparations performed using MED, CyDs have been used as chiral selectors except in one case [85] in which a chiral crown ether, (—)-(18-crown-6)-tetracarboxylic acid (18C6H4), was used as an effective chiral selector for resolving gemifloxacin in sodium-containing media. 

Crown ethers are synthetic macrocyclic polyethers that can form selective complexes with various cations. Chiral crown ethers such as (diphenyl-substituted l,l -binaphthyl) crown ether or (-Fill 8-crown-6)-2,3,11,12-tetracarboxylic acid, which are bound to silica gels or coated on reversed-phase materials, were utilized for the enantioseparation of underivatized primary amino acids and their esters. On the other hand, the enantiomers of underivatized and derivatized amino acids enter into... 

Extending the scope of combined chiral selector systems beyond CDs, one may note that this mode has been used in CE for a rather long time [53-56], The very first example of combined chiral selectors in CE seems to be the report by Fanali et al. [53] in 1989 when 15 mM L-(+)-tartaric acid buffer was used in combination with 15 mM P-CD in order to resolve the enantiomers of chiral cobalt complexes. CDs have also been combined with chiral surfactants such as cholic acids [54, 55] and synthetic micelle-forming agents [56], In recent years, several studies were published on the combination of CDs with chiral [57, 58] and achiral [51, 59-61] crown ethers. The latter studies [59-62] where the achiral crown ether cannot contribute to enantioseparations independently clearly illustrate that the simplified approach described in [12, 47] may not be universally applied to all dual chiral separation systems in CE. 

Armstrong DW, Chang LW, Chang SSC (1998) Mechanism of capilltiry electrophoresis enantioseparations using a combination of an achiral crown ether plus cyclodextrins. 1 Chromatogr A 793 115-134... 

Chromatographic enantioseparations may be performed using two methods called direct and indirect. In this former method, chiral stationary phases (polymers of natural origin, protein phases, synthetic polymers with build-in chiral selectors, etc.) are used or appropriate chiral selectors (cyclodextrins, crown ethers, etc.) are added to the mobile phase [7]. 

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