For enantioseparation

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Fig. 3-7. Evaluation of a focused library of 71 DNB-dipeptide CSPs for enantioseparation of the test racemate 8. (Reprinted with permission from ref. [86], Copyright 1999, American Chemical Society.)...

Fig. 4-2. Screen of REGISTER (data registration tool for enantioseparations).

This presentation covers some aspects of stereochemistry of the drags that are marketed and administered as racemic mixtures with an emphasis on status of analytical chemistry methods for enantioseparation and control of enantiomeric purity. There is also a brief discussion on related historical knowledge. 

In a comparable system, (I ,S)-ibuprofen can be separated by a membrane reactor [83], see Fig. 13.10. The technique comprises a stereo-specific hydrolysis by an enzyme. Subsequently, the enantiomeric ester is extracted into the organic phase on the other side of the membrane. In the system developed by Sepracor Inc., (i )-ibuprofen is selectively hydrolyzed by proteases in a hollow-fiber unit and the (S)-ibuprofen ester can be isolated at 100% yield. This configuration also applies for enantioseparation of other acids such as naproxen and 2-chloropropionic acid. 

A further modification is the creation of polymers out of CDs, which are also used for enantioseparations (20-22). They are obtained by radical copolymerization and often exhibit enormous solubility (23). 

Since one or more of the interactions in these systems might originate from the stationary phase, only a two- or a one-point interaction between the solute and the selector is necessary for mechanisms (2) and (3) to occur [50]. However, some of the CMPAs used in HPLC [37,40,51,52] have also been used as chiral selectors in CE [53-56], which indicates that at least one of the separation mechanisms between the selector and enantiomers is selective complex formation in the mobile phase in these cases, since there is no stationary phase present in CE. A recent example by Yuan et al. [57] is presented in Eigure 17.1. The authors introduced the use of (R)-A,A,A-trimethyl-2-aminobutanol-bis(trifluoromethane-sulfon)imidate as the chiral selector for enantioseparation in HPLC, CE, and GC. This chiral liquid serves simultaneously as a chiral selector and a co-solvent. 

Another practical guide for enantioseparation of pharmaceuticals with the most common types of CSPs has recently been published in a review by Thompson [34]. For polysaccharide and... 

In contrast to the various CSPs mentioned so far, but still based on covalently or at least very strongly adsorbed chiral selectors (from macromolecules to small molecules) to, usually, a silica surface, the principle of dynamically coating an achiral premodified silica to CSPs via chiral mobile phase additives (CMPA) has successfully been adapted for enantioseparation. The so-called reverse phase LC systems have predominantly been used, however, ion-pairing methods using nonaqueous mobile phases are also possible. 

TABLE 2-1. Physicochemical Properties of Glycopeptide Antibiotics Used for Enantioseparation... 

Co(acac)3 is frequently used as a probe for enantioseparation efficiency of col-umns " . A monolytic capillary silica gel column was functionalized with methacrylate residues in two steps, as shown in equation and then it was impregnated with cellulose or amylose (51a, b) which was modified so that 30% of the R groups were the methacrylate group 52 and the rest was identical to R (53). For further stability of the column, the polymeric modifier was immobilized on the silica gel by in situ copolymerization with an olefinic monomer such as 2,3-dimethylbutadiene. Only the column containing cellulose modified as in 51a was able to separate the Co(acac)3 racemic mixture, whereas neither cellulose nor amylose modified as in 51b did, although they were successful in resolving other racemic mixtures ° °. ... 

For charged CSPs, non-directed and long-ranged ionic interactions will drive the first contact between SA and SO followed by additional SO-SA binding forces. It is expected that this primary interaction turns out to be non-stereo.selective, thus being of similar strength for both (R)-SA- (S)-SO and (5)-SA- (S)-SO complexes. For enantioseparation, additional and spatially controlled intermolecular SO-SA interactions have to come into force. 

A collection of recent applications of CLEC systems for enantioseparation is given in Table 9.17. 

The majority of enantioseparations are performed by pressure-driven liquid chromatography. However, in the last decade other liquid-phase separation techniques have evolved and demonstrated their usefulness for enantioseparations, including supercritical fluid chromatography (SFC), capillary electrophoresis (CE), micellar electrokinetic chromatography (MEKC), and open-tubular and packed-bed electrochromatography (OT-EC and CEC). 

More recently, capillary electrochromatography (CEC) has been adapted for enantioseparation concepts. In this separation method, the driving force for solute transport through the capillary columns is the electroosmotic flow (EOF) in addition, for charged SAs, an electrophoretic transport increment has also to be considered. The enantioseparation occurs due to differential distribution of the SA-enantiomers to the immobilized chiral SO moieties, or in the additive mode due to differential migration of diastere-omeric SO-SA a.ssociates and/or their differential distribution onto an achiral stationary phase. Thus, the following strategies have been adopted for CEC enantioseparations,... 

Shao, P., Ji, G., and Chen, P., Gold nanotube membranes Preparation characterization and appheation for enantioseparation, J. Membr. 

The chromatographic separation of enantiomers, often referred to as enantioseparation, has received a great deal of attention in recent years. Both liquid (LC) and gas (GC) chromatographic procedures are used. The former is extremely useful for enantioseparations because of the available variations in scale, mechanism, and technique. It has been used in enantioseparations from analytical to preparative in scale, taking advantage of various modes of diastereoisomeric interactions andusing elution and displacement techniques. All the chromatographic methods involve diastereoisomeric interactions between the enantiomers of interest and... 

The ligand-exchange process has been applied as a mobile-phase-additive technique for enantioseparations. It involves the formation of a dissociable diastereoisomeric complex between a homochiral additive and a heterochiral solute about a central metal ion (Fig. 28). The mobile phase contains both the homochiral ligand and the metal ion as additive components. These species probably exist as the fully complexed species with at least two molecules of the homochiral... 

For enantioseparation chiral stationary phases (CSPs), an expression of the relative selectivity is obtained ... 

For enantioseparation with chiral additives in CEC, we derived another expression ... 

For enantioseparation on CSPs in CEC, nonstereospecific interactions, expressed as 4>K, contribute only to the denominator as shown in Eq. (1), indicating that any nonstereospecific interaction with the stationary phase is detrimental to the chiral separation. This conclusion is identical to that obtained from most theoretical models in HPLC. However, for separation with a chiral mobile phase, (pK appears in both the numerator and denominator [Eq. (2)]. A suitable (f)K is advantageous to the improvement of enantioselectivity in this separation mode. It is interesting to compare the enantioselectivity in conventional capillary electrophoresis with that in CEC. For the chiral separation of salsolinols using /3-CyD as a chiral selector in conventional capillary electrophoresis, a plate number of 178,464 is required for a resolution of 1.5. With CEC (i.e., 4>K = 10), the required plate number is only 5976 for the same resolution [10]. For PD-CEC, the column plate number is sacrificed due to the introduction of hydrodynamic flow, but the increased selectivity markedly reduces the requirement for the column efficiency. 

Guaran is a polygalactomannan containing T-OH groups. It is well known that the tetrahedral borate ions readily form tetrahedral complexes with the cw-OH groups. Thus the borate immobilized polymer (boron content 0.7 mmol/g) was used for enantioseparation of racemates such as 1,2- or 1,3-dihydroxy compounds or a-hydroxy acids.This appears to be the first example of the use of boron as a complexing ion in CLEC. 

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