Chiral separation-based methods

A variety of strategies have been devised to obtain chiral separations. Although the focus of this article is on chromatographicaHy based chiral separations, other methods include crystallisation and stereospecific ensymatic-catalysed synthesis or degradation. In crystallisation methods, racemic chiral ions are typically resolved by the addition of an optically pure counterion, thus forming diastereomeric complexes. 

Another example in Fig. 7 shows the chiral resolution obtained in electro-kinetic chromatography using vancomycin as a chiral selector (Fig. 7a), and the chiral selectivity observed in HPLC separations using a sulfated j8-cyclodextrin stationary phase (Fig. 7b). In both cases, the differences observed from fluorescence anisotropy follow very similar trends as those obtained from the separation-based methods. 

Possible applications of MIP membranes are in the field of sensor systems and separation technology. With respect to MIP membrane-based sensors, selective ligand binding to the membrane or selective permeation through the membrane can be used for the generation of a specific signal. Practical chiral separation by MIP membranes still faces reproducibility problems in the preparation methods, as well as mass transfer limitations inside the membrane. To overcome mass transfer limitations, MIP nanoparticles embedded in liquid membranes could be an alternative approach to develop chiral membrane separation by molecular imprinting [44]. 

Matthijs, N., Perrin, C., Maftouh, M., Massart, D.L., Vander Heyden, Y. Knowledge-based system for method development of chiral separations with capillary electrophoresis using highly sulphated cyclodextrins. J. Pharm. Biomed. An. 2002, 27, 515-529. 

Geiser et al. [50,51] illustrated the screening of different chiral stationary phases and the separation of highly polar amine hydrochlorides using EEL methanol/C02 mixtures and the columns, Chiralpak-AD-H, Chiralpak-AS. This method is advantageous because no acid or base additive was required to achieve base line separation of the racemates and conversion to free base form for enantiomer separation was not required. Preparative-scale separations of the amine-hydrochloride were accomplished using similar mobile phase conditions [51], Furthermore, this is believed to be the first chiral separation of highly polar solutes without the addition of acid or base additive to effect the separation. 

CR Mitchell, DW Armstrong. Cyclodextrin-based chiral stationary phases for liquid chromatography A twenty-year overview. In G Gubitz, MG Schmid (Eds.) Chiral Separations, Methods and Protocols, Humana Press Inc., Totowa, NJ Humana Press Inc. 61 pp., 2003. 

Abou-Basha and Aboul-Enein [22] presented an isocratic and simple HPLC method for the direct resolution of the clenbuterol enantiomers. The method involved the use of a urea-type CSP made of hS )-indoline-2-carboxylic acid and (R)-1 -(naphthyl) ethylamine known as the Chirex 3022 column. The separation factor (a) obtained was 1.27 and the resolution factor (Rs) was 4.2 when using a mobile phase composed of hexane-1,2-dichloroethane-ethanol (80 10 10, v/v/v). The (+)-enantiomer eluted first with a capacity factor (k) of 2.67 followed by a (—)-enantiomer with a k of 3.38. Biesel et al. [23] resolved 1-benzylcyclohexane-1,2-diamine hydrochloride on a Chirex D-penicillamine column. Gasparrini et al. [24] synthesized a series of the chiral selectors based on /ra s -1,2 - d i a m i n o eye I o hexane. The developed CSPs were used for the chiral resolution of arylacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, tertiary phosphine oxides, and benzodiazepines. In another study, the same authors [25] described the chiral resolution of /i-aminocstcrs enantiomers on synthetic CSPs based on a re-acidic derivatives of trans- 1,2-diaminocyclohexane... 

Chiral separation by HPLC is a practically useful method not only for determining optical purity but also for obtaining optical isomers, and numerous CSPs are presently on the market. In order to achieve the efficient resolution of chiral compounds, we have to choose a suitable chiral column and eluent. The polysaccharide-based CSPs have a high chiral recognition ability and offer a high possibility for the successful resolution of racemates including aliphatic and aromatic compounds with or without functional groups under normal and reversed-phase conditions. 

This is the second important contribution of Kagan s group in the synthesis of chiral sulfoxides. The method was reported in 1989 for the synthesis of tert-butyl sulfoxides,90 and the full paper on the generalization of the method was published in 1991.86 The approach is based on the synthesis and use of an o.p. cyclic sulfite in the synthesis of various sulfoxides by two successive condensations of two organometallic reagents, RjM and R2M. Thus, the sulfoxides are produced in three separate steps the formation of cyclic sulfite, synthesis of sulfinate esters, and transformation of sulfinates to chiral sulfoxides. 

Chiral polymers have been applied in many areas of research, including chiral separation of organic molecules, asymmetric induction in organic synthesis, and wave guiding in non-linear optics [ 146,147]. Two distinct classes of polymers represent these optically active materials those with induced chirality based on the catalyst and polymerization mechanism and those produced from chiral monomers. Achiral monomers like propylene have been polymerized stereoselectively using chiral initiators or catalysts yielding isotactic, helical polymers [148-150]. On the other hand, polymerization of chiral monomers such as diepoxides, dimethacrylates, diisocyanides, and vinyl ethers yields chiral polymers by incorporation of chirality into the main chain of the polymer or as a pedant side group [151-155]. A number of chiral metathesis catalysts have been made, and they have proven useful in asymmetric ROM as well as in stereospecific polymerization of norbornene and norbornadiene [ 156-159]. This section of the review will focus on the ADMET polymerization of chiral monomers as a method of chiral polymer synthesis. 

Method development for chiral separation is a multidisciplinary task. It requires knowledge of stereochemistry, organic chemistry, and separation techniques. Separation of enantiomers is not linked to a certain technique (i.e., GC, HPLC, etc.) but rather to an understanding of the specific interactions between the enantiomeric analytes and a certain chiral stationary phase. Knowing these types of relationships will enable one to easily understand the formation of transient diastereomeric complexes between enantiomers and a chiral stationary phase during a chromatographic separation as well as their stereochemical relationship within the complex. Once such dependencies are established, development of a method for the separation of enantiomers becomes an easy process. Based on such a relationship, chiral stationary phases can be divided in five categories [161] ... 

J. Haginaka, Y. Okazaki, and H. Matsunaga, Separation of enantiomers on a chiral stationary phase based on ovoglycoprotein. V. Influence of immobilization method on chiral separation, J. Chromatogr. 840 (1999), 171. 

Arnold and co-workers have developed an approach that allows both the imprinting and the subsequent chiral separation of free amino acids to be carried out in aqueous solutions [39]. The recognition was based on metal coordination-chelation interactions using A-(4-vinylbenzyl)iminodiacetic acid as the functional monomer. (For a further discussion of this system see Chapters 6 and 9.) The method worked best for aromatic amino acids (Fig. 17.11). 

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