Chiral gels applications

Electrophoretic methods are widely used alternatives for the analytical determination of the enantiomeric purity of chiral compounds [194]. Due to the high elTi-ciency of capillary electrophoresis, separations can be achieved even when very low selectivities are observed. At a preparative scale, these methods are well established for the purification of proteins and cells [195] but there is very little published on enantioselective separations. Only recently, some interest in chiral preparative applications has been manifested. Separation of the enantiomers ofterbu-taline [196] and piperoxan [197] have been reported by classical gel electrophoresis using sulfated cyclodextrin as a chiral additive, while the separation of the enantiomers of methadone could be successfully achieved by using free-fluid isotachophoresis [198] and by applying a process called interval-flow electrophoresis [199]. 

Although some applications for preparative-scale separations have already been reported [132] and the first commercial systems are being developed [137, 138], examples in the field of the resolution of enantiomers are still rare. The first preparative chiral separation published was performed with a CSP derived from (S -N-(3,5-dinitrobenzoyl)tyrosine covalently bonded to y-mercaptopropyl silica gel [21]. A productivity of 510 mg/h with an enantiomeric excess higher than 95% was achieved for 6 (Fig. 1-3). 

The main limitation of these CSPs is their limited pressure stability, which makes them not very suitable for HPLC application. However, they have proved to be an excellent tool for the preparative separation of drugs by low-pressure HPLC. To make these CSPs accessible to HPLC, silica gel-based phases were developed. " This type of phase is available from Merck (Darmstadt, Germany) under the name Chiraspher. Polymer phases of different types have been developed by Okamoto s group. > They are prepared by the asymmetric polymerization of triphenylmethyl-methacrylate monomers. The original character of these polymers is that they do not possess any chiral centre and therefore their chirality is only due to their helicity. However, clear mechanisms have not been proposed... 

Among the electrophoretic methods of chiral resolution, various forms of capillary electrophoresis such as capillary zone electrophoresis (CZE), capillary isotachophoresis (CIF), capillary gel electrophoresis (CGE), capillary isoelectric focusing (CIEF), affinity capillary electrophoresis (ACE), and separation on microchips have been used. However, in contrast to others, the CZE model has been used frequently for this purpose [44]. On the other hand, drawbacks associated with the electrophoretic technique due to lack of development of modem chiral phases have limited the application of these methods. Moreover, the electrophoretic techniques cannot be used at the preparative scale, which represents an urgent need of chiral separation science. 

In 1998, Machida et al. [45] and Hyun et al. [46] developed a new CCE-based CSP (covalently bonded to silica gel see Sect. 8.2). This CSP was used successfully for the chiral resolution of certain racemic compounds using a variety of mobile phases. The most important applications of this CSP are for the resolution of amino acids, amino esters, amino alcohols, amines, amides, quinolone antibacterials, and other drugs having primary amino groups [46-51,64,65]. The typical chromatograms of the chiral resolution of amino acids on (+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid CSP are shown in Figure 4. The enantiomeric resolution of the racemic compound on CCE-based CSPs are listed in Table 2. There is no report available on the chiral separations at the preparative scale using these CSPs. 

The synthesis of optically active polymers is an important area in macromolecular science, as they have a wide variety of potential applications, including the preparation of CSPs [31-37]. Many of the optically active polymers with or without binding to silica gel were used as CSPs and commercialized [38]. These synthetic polymers are classified into three groups according to the methods of polymerization (1) addition polymers, including vinyl, aldehyde, isocyanide, and acetylene polymers, (2) condensation polymers consisting of polyamides and polyurethanes, and (3) cross-linked gels (template polymerization). The art of the chiral resolution on these polymer-based CSPs is described herein. 

Generally, cross-linked polymers recognize chiral resolution through chiral cavities. Some polymers were synthesized and used for chiral resolution purposes [79-82], The applications of these CSPs include the chiral resolution of amino acids, /1-blockers, and profens. Wulf et al. [83] observed that the chiral resolution capacity of these gels is significantly affected by the kind and amount of crosslinker agent. 

Chiral porous materials have many applications in separation science and catalysis.22 Marx and Avnir have described chirality in sol-gel materials, with a particular focus on their work.31 In this section, an overview of some of this work is given, with emphasis on the use of chiral templates to create materials that demonstrate enantioselectivity. 

Few synthetically useful examples of the oxidation of ethers by oxygen or ozcne have been publish-ed. In 1978, Ourisson and coworkers reported that ozonization of the natural product cedrane oxide (43) on silica gel at -78 °C led to the formation of the corresponding lactone 44) in 30% yield (equation 32). A small amount of the tertiary alcohol (45) was also produced. Later, in the course of a chiral total synthesis of compactin, Hirama examined the ozonolysis of the alkene (46 equation 33). Under carefully controlled conditions, selective ozonolysis of the double bond could be achieved in 88% yield. However, when excess ozone was employed, significant amounts of the benzoate (47) were obtained, even at -78 C. In subsequent studies, benzyl ethers of primary and secondary alcohols, and carbohydrates were oxidized to the corresponding benzoates in excellent yields. Surprisingly, no further synthetic applications of this reaction have been reported. 

Chiral poly(meth)acrylamides as CSPs. In 1974, Blaschke reported the preparation and application of soft cross-linked poly(meth)acrylamide polymeric beads (11), which were synthesized by suspension polymerization from acryl or methacrylamides with chirality residing in the side chain of the amine component. Mechanically more stable chiral sorbents have subsequently been produced by polymerizing and covalently anchoring the monomers onto the surface of silica gels [ 192). The CSP obtained by this procedure from A -acryloyl-(S)-phenylalanine ethyl ester as monomer is commercialized by Merck under the tradename ChiraSpher. 

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