Cyclodextrin derived CSPs

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodextrin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

CSPs, cyclodextrin-derived CSPs, " antibiotic-derived CSPs, " and protein-derived CSPs. As a general rule, starting conditions are applied to set retention of the analyte, and in the next step, enantioselectivity is tuned by stepwise modifying appropriate factors, considering the chemical nature of the analyte, compatibility with the chromatographic support, and recognition mechanism acting in the separation. 

The type of CSPs used have to fulfil the same requirements (resistance, loadabil-ity) as do classical chiral HPLC separations at preparative level [99], although different particle size silica supports are sometimes needed [10]. Again, to date the polysaccharide-derived CSPs have been the most studied in SMB systems, and a large number of racemic compounds have been successfully resolved in this way [95-98, 100-108]. Nevertheless, some applications can also be found with CSPs derived from polyacrylamides [11], Pirkle-type chiral selectors [10] and cyclodextrin derivatives [109]. A system to evaporate the collected fractions and to recover and recycle solvent is sometimes coupled to the SMB. In this context the application of the technique to gas can be advantageous in some cases because this part of the process can be omitted [109]. 

Cyclodextrin-based CSPs are among the most popular materials used for the chiral resolution of racemic compounds. These CSPs have a wide range of applications because they can be used successfully in all three mobile phase modes normal, reversed, and polar organic. There are numerous examples of chiral separations on CDs and CSPs based on their derivatives. Some of the important chiral separations are discussed herein. 

In 1978, Harada et al. [17] used polymerized CD with gel support for the chiral resolution of mandelic acid and its derivatives. Later Zsadon et al. [18-21] used cyclodextrin-based CSPs for the chiral resolution of indole alkaloids, with aqueous buffers as the mobile phases. Today CD-based CSPs have a good reputation. In separate studies, Fujimura [22] and Kawaguchi [23] and their colleagues resolved the enantiomers of aromatic compounds in the reversed-phase mode. Armstrong et al. [29,30,33,34,41,44 46,48,54-63] carried out extensive and remarkable work on the chiral resolution of various racemic compounds using CD-based CSPs. 

FIGURE 15 The chemical structures of some CSP-based a- and /1-cyclodextrin derivatives. (From Ref. 49.)... 

FIGURE 16 The chemical structures of some drugs resolved on different CSPs based on a- and /1-cyclodextrin derivatives (Fig. 15) Troger s base (I), tra .s-2,.1-diphenyloxirane (II), l-(9-anthryl)-2,2,2-trifluoroethanol (III), 1,2,2,2-tetraphenylethanol (IV), 2,2 -dihy-droxy-6,6-dimethylbiphenyl (V), 2-phenylcyclohexanone (VI), flavanone (VII), benzoin (VIII), and tnms -cyclopropanedicarboxylic acid anilide (IX). (From Ref. 49.)... 

Aroma compounds originate from biosynthetic pathways inside an animal, a botanical body, and other life-forms as well as enzymes and thus frequently carry chiral components within the molecule. Determination of such enantiomeric properties can, in many cases, be accomplished using a GC column with a chiral stationary phase (CSP) application.75-79 These columns, usually called chiral GC column, will provide diastereometric interaction that could lead to resolution of enantiomers. Commercially available chiral GC columns predominantly utilize cyclodextrin derivatives as CSPs. Chiral columns consisting of multiple cyclodextrin derivatives intending synergic effect in resolution property80 are also successful in the market. In practice, these columns are mainly operated as secondary columns in MDGC technique. 

GC on cyclodextrine type CSP of the O-TFA derivative of methyl lactate Analysis of methyl lactate O-TFA form. Good resolution between the two enantiomers Good reproducibility Requires double derivatization with the use of diazomethane 0.1 %... 

GC on cyclodextrine type CSP of a dioxolanone type derivative No racemization of the sample on derivatization Difficult integration of the peaks Derivatization of the sample < 0.5 %... 

Chromatograms corresponding to the separation of the enantiomers of derivatives of methyl and isobutyl esters of lactic acid are presented in Figure 11. The method developed is non racemizing and gives results comparable with those given by GC on cyclodextrine type CSP. 

Microcrystalline cellulose triacetate, cyclodextrin- and crown ether-derived CSPs, as well as some chiral synthetic polymers, achieve enantiomer separation primarily by forming host-guest complexes with the analyte in these cases, donor-acceptor interactions are secondary. Solutes resolved on cyclodextrins and other hydrophobic cavity CSPs often have aromatic or polar substituents at a stereocenter, but these CSPs may also separate compounds that have chiral axes. Chiral crown ether CSPs resolve protonated primary amines. 

Separation Technologies Inc., of Whippany, NJ, USA. In 1991, the same company received two global patents for the use of two specific cyclodextrin derivatives for the separation of enantiomers by capillary GC. This technology is known by the trade name of Chiraldex. Various Chiraldex columns have been developed, using the prefixes A, B and G for the a-, and y-CDs, respectively [92], Similarly, Supelco have also developed various chiral stationary phases under the trade name of Dex a-Dex, S-Dex and y-Dex CSPs on fused silica capillary columns containing premethylated a-, and y-CDs coupled to a phenyl that contains a stationary polysiloxane... 

Fig. 11 Separation of 12 chiral f -lactams on CD-CSPs. The cyclodextrin derivative codes are DMP ...

A CSP with a smaller (i-cyclodextrin moiety (seven glucose units) immobilized on silica gel (ChiraDex ) is able to separate the dansyl-derivatives [5-(dimethy-lamino)-naphthalin-l-sulfonylchloride] of amino acids [26]. 

In an attempt to change and broaden the capabilities of the vancomycin CSP, the glycopeptide was derivatized with (R)- and (S )-(l-naphthylethyl) isocyanate (NEIC) and then bonded to a silica-gel support [48]. A variety of chiral compounds was tested on the two composite stationary phases and the results were compared with the ones obtained using the underivatized vancomycin CSP. The advantages of the NEIC derivatization were not as obvious or substantial as they were in the case of cyclodextrin phases [49]. Moreover, the exact chemical structures of the synthesized NEIC derivatives of vancomycin were not reported. 

Enantioseparation of nine amphetamine derivatives, methorphan, and propoxyphene was studied by comparing two different CSP typologies, a macrocyclic antibiotic CSP (vancomycin) and a native P-cyclodextrin CSP [123]. The suitability of the eluent systems to ESI interfacing was discussed, and a tandem mass spectrometric (MS/MS) detection method was developed. 

Chen, S. and Ward, T., Comparison of the chiral separation of amino-acid derivatives by a teicoplaiun and RN-fS-cyclodextrin CSPs using waterless mobile phases factors that enhance resolution. Chirality, 16, 318, 2004. 

CMPA, CE MEKC CSP e.g. cyclodextrins, amino acids cholic acids, tartaric acids, alkaloids etc. and Derivatives Thereof analytical to preparative excellent, fair to moderate... 

Norbomene was functionalized with cyclodextrins and surface grafted onto silica-based supports using ROMP (44). The CSP are suitable for the enantioselective separation various amino acids, including jS-blockers and other compounds, such as chiral ferrocene derivates. 

The separation of enantiomers can be effected either by transforming them into diastereoisomers using a chiral reagent and separating them on conventional phases or by separating the enantiomers on chiral phases. The utilization of chiral phases has not yet become routine, but studies of enantiomeric dipeptides have been carried out (115,116). Pirkle et al. (117) and Hyun et al. (118) separated enantiomeric di- and tripeptides (methyl esters of /V-3-5-dinitrobenzoyl derivatives) on chiral stationary phases (CSPs) derived from (R)-a-arylalkylamines, (S)-N-(2-naphthyl) valine, or (S)-1 -(6,7-dimethyl-1 -naphthyl) isobutylamine. These workers were able to separate four peaks for each dipeptide derivative, corresponding to the two enantiomeric pairs (R,R)/(S,S) and (R,S)/(S,R). Cyclodextrin-bonded stationary phases and chiral stationary immobilized a-chymotrypsin phases were used to separate enantiomeric peptides (118a,b). 

Because the steric effect contributes to the complex formation between guest and host, the chiral resolution on these CSPs is affected by the structures of the analytes. Amino acids, amino alcohols, and derivatives of amines are the best classes for studying the effect of analyte structures on the chiral resolution. The effect of analyte structures on the chiral resolution may be obtained from the work of Hyun et al. [47,48]. The authors studied the chiral resolution of amino alcohols, amides, amino esters, and amino carbonyls. The effects of the substituents on the chiral resolution of some racemic compounds are shown in Table 6. A perusal of this table indicates the dominant effect of steric interactions on chiral resolution. Furthermore, an improved resolution of the racemic compounds, having phenyl moieties as the substituents, may be observed from this Table 6. ft may be the result of the presence of n—n interactions between the CCE and racemates. Generally, the resolution decreases with the addition of bulky groups, which may be caused by the steric effects. In addition, some anions have been used as the mobile phase additives for the improvement of the chiral resolution of amino acids [76]. Recently, Machida et al. [69] reported the use of some mobile phase additives for the improvement of chiral resolution. They observed an improvement in the chiral resolution of some hydrophobic amino compound using cyclodextrins and cations as mobile phase additives. 

---