Enantioselective separation, fundamental

Enantioselective separation by supercritical fluid chromatography (SFC) has been a field of great progress since the first demonstration of a chiral separation by SFC in the 1980s. The unique properties of supercritical fluids make packed column SFC the most favorable choice for fast enantiomeric separation among all of the separation techniques. In this chapter, the effect of chiral stationary phases, modifiers, and additives on enantioseparation are discussed in terms of speed and resolution in SFC. Fundamental considerations and thermodynamic aspects are also presented. 

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

The production of enantiomerically pure chemicals is one of the more demanding and important challenges in chemical research, both at fundamental and at applied levels. Enantioselective synthesis and racemate separation rely on specific interactions between a chiral phase and a substrate. Thus, molecular modeling may be applied to the design of new, highly efficient, chiral phases that are able to selectively... 

The fundamental principle of enantioselective HPLC is based on the formation of labile diastereomeric complexes of the two enantiomers with the chiral selector of the stationary phase [3], The enantiomer that forms the less stable complex will be eluted earlier, while the enantiomer that forms the more stable complex will be eluted later. The ratio of the two retention factors k determines the separation factor for the enantioselectivity [4] a (Eq. 1) of a stationary phase for two enantiomers at a certain temperatrue and for a defined solvent composition. 

The differences between achiral and enantioselective HPLC are smaller than is generally assumed. Enantioselective HPLC does not require special units or detectors, and all physico-chemical fundamentals of the chromatography are identical. However, it should be noted that many of the described enantioselective HPLC separations are performed imder normal-phase conditions. Applications of the popular water/mefhanol or water/acetonitrile gradients are in the minority, since many CSPs are not compatible with these gradient systems or do not show any retention. 

The fundamentals introduced in the previous sections allow some conclusions regarding optimization of enantioselective HPLC separations. 

The studies presented in this chapter clearly demonstrate the potential that exist for using fluorescence anisotropy to study chiral recognition in CD-based systems, which has ramifications from both fundamental and applied perspectives. For example, preliminary work in our laboratory has already shown the potential of using the system for evaluating and optimizing chiral separation system a priori [39]. Other areas worthy of pursuit lie in further investigation of the method for determination of enantiomeric excess and the determination of enantioselective thermodynamic parameters, primarily in terms of increasing the precision and sensitivity of the measurements. 

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