Chiral phases cyclodextrins

More recently alkylated cyclodextrins have been developed as chiral phases. These phases are based on cyclodextrins, which are cyclic structures formed from 6, 7 or 8 glucose units. Alkylation of the hydroxyl groups in the structure of the cyclodextrins lowers their melting points and makes them suitable as GC phases. The cyclodextrins contain many chiral centres and separate enantiomers of drugs according to how well they fit into the chiral cavities of the cyclodextrin units (see Ch. 12 p. 273). 

Many types of chiral stationary phase are available. Pirkle columns contain a silica support with bonded aminopropyl groups used to bind a derivative of D-phenyl-glycine. These phases are relatively unstable and the selectivity coefficient is close to one. More recently, chiral separations have been performed on optically active resins or cyclodextrins (oligosaccharides) bonded to silica gel through a small hydrocarbon chain linker (Fig. 3.11). These cyclodextrins possess an internal cavity that is hydro-phobic while the external part is hydrophilic. These molecules allow the selective inclusion of a great variety of compounds that can form diastereoisomers at the surface of the chiral phase leading to reversible complexes. 

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). 

Neutral cyclodextrins have been used as chiral phase-transfer catalysts for an interesting inverse phase-transfer catalysis reaction [50]. The Markovnikovhydration of the double bond by an oxymercuration-demercuration reaction has been demonstrated in the presence of cyclodextrins as chiral phase-transfer catalysts to obtain products in low to moderate enantioselectivity (Scheme 7.16). The mercuric salts are water-soluble, and remain in the aqueous phase, whereas the neutral alkenes prefer an organic phase. A neutral cyclodextrin helps to bring the alkenes into the aqueous phase in a biphasic reaction, and also provides the necessary asymmetric environment. 

In the initial experiments reported here we did not attempt to optimize the separation in terms of yield and production rate. Rather, cur intent was to demonstrate that displacement chromatographic separations are feasible on a chiral stationary phase, cyclodextrin-silica, and gather preliminary information regarding the structure of displacers which cam De used with cyclodextrin-sil icas. The method development sequence described in the previous paragraph will be followed in the discussion of the results. 

Silica-base stationary phases have also been employed for enantiomeric separations in CEC [6,72-81]. In the initial work on chiral CEC, commercially available HPLC materials were utilized, including cyclodextrins [6,74,81] and protein-type selectors [73,75,80] such as human serum albumin [75] and ai-acid glycoprotein [73]. Fig. 4.9, for example, depicts the structure of a cyclodextrin-base stationary phase used in CEC and the separation of mephobarbital enantiomers by capillary LC and CEC in a capillary column packed with such a phase. The column operated in the CEC mode affords higher separation efficiency than in the capillary LC mode. Other enantiomeric selectors are also use in CEC, including the silica-linked or silica-coated macrocyclic antibiotics vancomycin [82,83] and teicoplanin [84], cyclodextrin-base polymer coated silicas [72,78], and weak anion-exchage type chiral phases [85]. Relatively high separation efficiency and excellent resolution for a variety of compounds have also been achieved using columns packed with naproxen-derived and Whelk-0 chiral stationary phases linked to 3 pm silica particles [79]. Fig. 4.10 shows the... 

Chiral chromatography methods are considered by many to be superior to conventional methods in that, besides analytical applications, they offer the greatest potential for the preparation of optically pure forms of the isomers [5,27,28]. In these examples the third chiral species is an integral part of the LC (or GC) system and may appear as a plain stationary phase (cyclodextrins),... 

Enantiomeric analysis of a new antiinflammatory agent in rat plasma using a chiral p-cyclodextrin stationary phase" (71). The R,R S,S enantiomers of the investigational antiinflammatory agent trans-6,6a,7,10, 10a,ll-hexahydro-8,9-dimethyl-U-oxodibenz[b,e]-oxepin-3-acetic add (HOA) were resolved on the p-CD CSP after extraction from rat plasma. The mobUe phase was a mixture of 0.05 M potassium dihydrogenphosphate (pH 5.3) and methanol (35 65, v/v) the flow rate was 1.0 mL/min and the temperature was 22 1 C. The results of the study indicated that the inactive (—) enantiomer was cleared from the plasma more rapidly than the active (+) isomer. 

Figure 2.10 Example of a separation with a chiral phase which contains cyclodextrins. The use of a chiral column to separate a racemic mixture of compounds leads to a splitting of the chromatogram signals as can be seen clearly for alcohols, 2 and 4. This chromatogram in isothermal mode, allows the calculation of retention indexes for the separated compounds (adapted from a Supelco illustration).

Cyclodextrin bonded phases. Cyclodextrins are cyclic chiral carbohydrates composed of six, seven or eight glucopyranose units the a-, and 7-cyclodextrins, respectively. Only the /3-cyclodextrins have been found to be of use in chiral chromatography. The monomers are configured... 

Capillary Electrophoresis Mobile phase Cyclodextrin Derivatives Chiral Surfactants (MEKC) Poly(saccharides) Glycopeptides Proteins Metal Chelates... 

Enantioselective Reductions. NaBH4 has been employed with less success than LiAULt or BH3 in enantioselective ketone reductions. Low to moderate ee values have been obtained in the asymmetric reduction of ketones with chiral phase-transfer catalysts, chiral crown ethers, -cyclodextrin, and bovine serum albumin. On the other hand, good results have been realized in the reduction of propiophenone with NaBH4 in the presence of isobutyric acid and of diisopropylidene-D-glucofuranose (ee = 85%), " or in the reduction of cr-keto esters and -keto esters with NaBHa-L-tartaric acid (ee >86%). ... 

Consider the separation of the isomers of 2-butanol, on the (2,6-di-0-pentyl-3-trifluoroacetyl-Y-cyclodextrin) depicted in figure 6.7. This cyclodextrin derivative is designed to provide strong polar interactions round the chiral centers of the cyclodextrin, so that the isomer that approaches closest to the chiral phase, experiences the maximum polar forces to selectively retain it in the column. 

D.W. Armstrong, W. DeMond, A. Alak, W.L. Hinze, T.E. Riehl and T. Ward, Liquid Chromatographic Separation of Enantiomers Using a Chiral P-Cyclodextrin-Bonded Stationary Phase and Conventional Aqueous-Organic Mobile Phases, Anal. Chem., 57(1985)237. 

A.M. Krstulovic, J.M. Gianviti, J.T. Burke and B. Mompon, Enantiomeric Analysis of a New Antiinflammatory Agent in Rat Plasma Using a Chiral P-Cyclodextrin Stationary Phase, J. Chromatogr., 426(1988)417. 

H.Y. Aboul-Enein, MR. Islam and S.A. Bakr, Direct HPLC Resolution of Racemic Nomifensine Hydrogen Maleate Using a Chiral Beta-Cyclodextrin-Bonded Stationary Phase, J. Liq. Chromatogr., 11 (7)(1988)1485. 

C. Pham-Huy, B. Radenen, A. Sahui-Gnassi and J. Claude, High-performance Liquid Chromatographic Determination of (S)- and (R)-propranolol in Human Plasma and Urine With a Chiral P-Cyclodextrin Bonded Phase, J. Chromatogr. B., 665(1995)125. 

Chiral Stationary Phases for Gas Chromatography Small Molecule Stationary Phases Chiral Polysiloxane Stationary Phases Chiral Metal Chelating Stationary Phases Cyclodextrin Chiral Stationary Phases... 

Protein Based Stationary Phases The Pirkle Type Stationary Phases Coated Cellulose and Amylose Derivatives Macrocyclic Glycopeptide Stationary Phases Cyclodextrin Based Chiral Stationary Phases Synopsis References Chapter 9... 

The presence of asymmetric carbons in selenomethionine, other a-selenoamino acids, and related compounds produces different chiral enantiomers with different physiological activities. HPLC separation of enantiomers is possible with a range of chiral stationary phases, d- and 1-Selenomethionine enantiomers have been resolved with an a-cyclodextrin stationary phase and other species with a teicoplanin-based chiral phase. Hybrid chiral methodologies based on GC, HPLC, and capillary electrophoresis, coupled with ICP-MS are feasible. Enantiomers of d,l-selenocystine, d,l-selenomethio-nine, and d,l-selenoethionine were examined in a range of commercial dietary supplements using a chiral crown ether stationary phase and ICP-MS detection. Selenium-em-iched onion, garlic, and yeast were analyzed and some of the selenoamino acid enantiomers were identified. l-Fluoro-2, 4-dinitro-phenyl-5-l-alanine amide was used to derivatize enantiomers of selenoamides for enhanced resolution. 

As in GC, the uses of LC for the separation of chiral species have significantly increased. Column materials now include chiral phases that may, for example, be based on monolithic silica columns with chemically bonded beta-cyclodextrin, teicoplanin, or cellulose tris(3,5-dimethylphenylcarbamate). Hydro-phobic amino compounds have been separated by LC using a crown ether dynamically coated chiral stationary phase. 

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