Cyclodextrins, chiral recognition

Cyclodextrins are macrocyclic compounds comprised of D-glucose bonded through 1,4-a-linkages and produced enzymatically from starch. The greek letter which proceeds the name indicates the number of glucose units incorporated in the CD (eg, a = 6, /5 = 7, 7 = 8, etc). Cyclodextrins are toroidal shaped molecules with a relatively hydrophobic internal cavity (Fig. 6). The exterior is relatively hydrophilic because of the presence of the primary and secondary hydroxyls. The primary C-6 hydroxyls are free to rotate and can partially block the CD cavity from one end. The mouth of the opposite end of the CD cavity is encircled by the C-2 and C-3 secondary hydroxyls. The restricted conformational freedom and orientation of these secondary hydroxyls is thought to be responsible for the chiral recognition inherent in these molecules (77). 

Although the chiral recognition mechanism of these cyclodexttin-based phases is not entirely understood, thermodynamic and column capacity studies indicate that the analytes may interact with the functionalized cyclodextrins by either associating with the outside or mouth of the cyclodextrin, or by forming a more traditional inclusion complex with the cyclodextrin (122). As in the case of the metal-complex chiral stationary phase, configuration assignment is generally not possible in the absence of pure chiral standards. 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

Chiral recognition of A-[Co(phen)3]3+ has been observed in a modified /3-cyclodextrin.772 Chiral discrimination has also been seen in photoinduced energy transfer from luminescent chiral lanthanoid complexes773 to [Co(phen)3]3+ and between photoexcited [Ru(bpy)3]2+ and [Co(phen)3]3+ co-adsorbed on smectite clays.774 The [Co(bpy)3]3+ ion has been incorporated into clays to generate ordered assemblies and also functional catalysts. When adsorbed onto hectorite, [Co(bpy)3]3+ catalyzes the reduction of nitrobenzene to aniline.775 The ability of [Co(phen)3]3+ to bind to DNA has been intensively studied, and discussion of this feature is deferred until Section 6.1.3.1.4. 

An understanding of the recognition of chirality at a molecular level has become of interest in many fields of chemistry and biology. In the past decade, many attempts to clarify the mechanism of chiral recognition on CSPs for liquid chromatography have been made by means of chromatography, NMR spectroscopy,199 202 X-ray analysis, and computational methods.203 - 206 The successful studies have been mostly carried out for the small-molecule CSPs, especially cyclodextrin-based CSPs and Pirkle-type (brush-type) CSPs. In contrast, only a few mechanistic studies on chiral discrimination at the molecular... 

The short-end injection was also used in a paper by Perrin et al. [28]. They saw a very high chiral recognition capability of highly sulfated cyclodextrins (HS-CD). Using a test set of 27 amino acid derivatives, the application of HS-a-CD, HS-fl-CD, and HS-y-CD in a 5% w/v concentration allowed the separation of 26 compounds, of which 22 had a Rs > 2. From their experiments, a screening and optimization scheme was derived (Figure 3.3), and based on this scheme, a separation strategy was defined... 

CE has been applied extensively for the separation of chiral compounds in chemical and pharmaceutical analysis.First chiral separations were reported by Gozel et al. who separated the enantiomers of some dansylated amino acids by using diastereomeric complex formation with Cu " -aspartame. Later, Tran et al. demonstrated that such a separation was also possible by derivatization of amino acids with L-Marfey s reagent. Nishi et al. were able to separate some chiral pharmaceutical compounds by using bile salts as chiral selectors and as micellar surfactants. However, it was not until Fanali first showed the utilization of cyclodextrins as chiral selectors that a boom in the number of applications was noted. Cyclodextrins are added to the buffer electrolyte and a chiral recognition may... 

B Chankvetadze, G Endresz, G Schulte, D Bergenthal, G Blaschke. Capillary electrophoresis and H NMR studies on chiral recognition of atropisomeric binaphthyl derivatives by cyclodextrin hosts. J Chromatogr A 732 143-150,... 

In summary, molecular modeling when used in combination with instrumental techniques, especially 1D-ROESY and X-ray crystallography, may significantly contribute to understanding the nature of the intermolecular forces responsible for chiral drug-cyclodextrin interactions and chiral recognition. 

S Sabah, GKE Scriba. pH-Dependent reversal of the chiral recognition of tripeptide enantiomers by carboxymethyl-/3-cyclodextrin. J Chromatogr A 833 261-266, 1999. 

K Kano, Y Tamiya, C Otsuki, T Shimomura, T Ohno, O Hayashida, Y Murakami. Chiral recognition by cyclic oligosaccharides. Enantioselective com-plexation of binaphthyl derivatives with cyclodextrins. Supramol Chem 2 137, 1993. 

A chiral selector can also be dissolved in the IL solvent and be subsequently coated on the capillary wall [38]. In this approach, the achiral [C4CiIm]Cl was used to dissolve permethylated p-cyclodextrin (p-PM) and dimethylated P-cyclodextrin (p-DM). The chromatographic separations obtained from these two columns were compared to two commercially available CSPs based on p-PM and p-DM dissolved in polydimethylsiloxane. From a set of 64 chiral molecules separafed by fhe commercial p-PM column, only 21 of the molecules were enantioresolved by the IL-based p-PM column. Likewise, from a collecfion of 80 analytes separated by the p-DM column, only 16 analytes could be separated on the IL-based p-DM column. The authors also noted a considerable enhancement in the separation efficiency of fhe IL-based CSPs. This resulf, coupled to fhe loss of enantioselecfivify for mosf separations, suggests that the imidazolium cation may occupy the cavity of the cyclodextrin preventing the analyte-cyclodextrin inclusion complex-ation that is crucial for chiral recognition. The ability for ILs to form inclusion complexes wifh cyclodextrin molecules has been recently studied by Tran and coworkers using near-infrared spectromefry [39]. 

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