Chiral selection

Limitations with the chiral selectivity of the native cyclodextrins fostered the development of various functionalized cyclodextrin-based chiral stationary phases, including acetylated (82,83), sulfated (84), 2-hydroxypropyl (85), 3,5-dimethylphenylcarbamoylated (86) and... 

Appllca.tlons. MCA is used for the resolution of many classes of chiral dmgs. Polar compounds such as amines, amides, imides, esters, and ketones can be resolved (34). A phenyl or a cycloalkyl group near the chiral center seems to improve chiral selectivity. Nonpolar racemates have also been resolved, but charged or dissociating compounds are not retained on MCA. Mobile phases used with MCA columns include ethanol and methanol. 

An interesting and practical example of the use of thermodynamic analysis is to explain and predict certain features that arise in the application of chromatography to chiral separations. The separation of enantiomers is achieved by making one or both phases chirally active so that different enantiomers will interact slightly differently with the one or both phases. In practice, it is usual to make the stationary phase comprise one specific isomer so that it offers specific selectivity to one enantiomer of the chiral solute pair. The basis of the selectivity is thought to be spatial, in that one enantiomer can approach the stationary phase closer than the other. If there is no chiral selectivity in the stationary phase, both enantiomers (being chemically identical) will coelute and will provide identical log(Vr ) against 1/T curve. If, however, one... 

Figure 3.7 shows some early examples of this type of analysis (39), illustrating the GC determination of the stereoisomeric composition of lactones in (a) a fruit drink (where the ratio is racemic, and the lactone is added artificially) and (b) a yoghurt, where the non-racemic ratio indicates no adulteration. Technically, this separation was enabled on a short 10 m slightly polar primary column coupled to a chiral selective cyclodextrin secondary column. Both columns were independently temperature controlled and the transfer cut performed by using a Deans switch, with a backflush of the primary column following the heart-cut. 

Figure 3.7 [continued) (b) Chromatograms of (iii) the dichloromethane extract of strawberry fruit yoghurt analysed with an apolar primary column, with the heart-cut regions indicated, and (iv) a non-racemic mixture of y-deca-(Cio) and 7-dodeca-Cj2 lactones isolated by heart-cut transfer, and separated by using a chiral selective modified cyclodextrin column. Reproduced from A. Mosandl, et al J. High Resol. Chromatogr. 1989, 12, 532 (39f. 

Column coupling proves to be a rapid screening approach in identifying chiral selectivity in the most efficient and economical way. In addition to the potential for the simultaneous analysis of a mixture, the coupling practice offers the advantages... 

Supercritical fluid chromatography (SFC) provides a means of minimizing the limitations of CSPs developed for FC while retaining the impressive chiral selectivity that has been achieved through the evolution of CSPs during the past two decades [6, 7]. The use of supercritical fluids as eluents for chromatographic separations was... 

Many racemic mixtures can be separated by ordinary reverse phase columns by adding a suitable chiral reagent to the mobile phase. If the material is adsorbed strongly on the stationary phase then selectivity will reside in the stationary phase, if the reagent is predominantly in the mobile phase then the chiral selectivity will remain in the mobile phase. Examples of some suitable additives are camphor sulphonic acid (10) and quinine (11). Chiral selectivity can also be achieved by bonding chirally selective compounds to silica in much the same way as a reverse phase. A example of this type of chiral stationary phase is afforded by the cyclodextrins. 

The main applications of CGE are in separating protein fractions and oligonucleotides, and for DNA sequencing. Cyclodextrins have been incorporated into some polymers to introduce chiral selectivity. 

In 1974 Garay and Hrasko [13] contended that PVEDs between enantiomers would, in the course of millions of years of evolution, lead to almost complete selection of one isomer, and in 1975 Letokhov [14] asserted that PVED-generated rate differences as small as 10-16 would over 10s to 109 years be quite sufficient for full selection of either of the two stereoisomeric forms of all the amino acids that occur in animate nature. In 1983 Kondepudi and Nelson [15] claimed that a value of AE/kTof 1017 to 1(T15 is sufficient to have a strong chiral selectivity. ... 

In this connection, the nature of the metal ion is expected to play an important role and the experimental data indeed show intriguing effects.In the case of amino acids, for example, Cu(ll) offers much larger chiral selectivity than does Zn(II) or Ni(II), which is due to the formation of a square planar structure. 

Table 11 Chiral selectivity factors, RPI /RPI = [U M ]" /[U Ms]4 (equation (25)) for chiral crown ethers complexed with enantiomeric alkylammonium ions (Ur .f = 6 in Scheme 5)...

Fig. 18 Chiral selectivity (ko/kL) as a function of the number of non-hydrogen atoms on the amino acid. Hosts permethylated j8-CD reagent base 1-propylamine. Chiral selectivity tends to increase with the size of the amino acids. Phe and Tyr, however, do not follow this trend.

In face of the above discouraging results, recent innovative catalyst work has led to highly effective solutions for some otherwise very difficult and expensive problems. For example. Dolling and co-workers (Chapter 7) have shown that by careful choice of PTC catalyst and use of optimal reaction conditions one can obtain high chiral selectivity (greater than 90% enantiomeric excess) and have applied this chemistry to a commercial process for production of the diuretic drug candidate Indacrinone. 

Rawjee, Y.Y., Stark, D.U., Vigh, G. Capillary electrophoretic chiral separations with cyclodextrin additives I. acids Chiral selectivity as a function of pH and the concentration of P-cyclodextrin for fenoprofen and ibuprofen. J. Chromatogr. 1993, 635, 291-306. 

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