Chiral Selectors For Enantiomeric Separation Research Articles

Performance comparison of chiral separation materials derived from N-cyclohexylcarbonyl and N-hexanoyl chitosans

Chitosan bis(phenylcarbamate)-(N-cyclohexylformamide)s and chitosan bis(phenylcarbamate)-(N-hexanamide)s were synthesized as chiral selectors for enantiomeric separation. Since two types of substituents with different structures were, respectively, introduced onto the 2-position and the 3-/6-positions of the glucose skeleton in the chitosans through a “heterogeneous” modification pathway, the enantioseparation performances of the chiral selectors could be improved. Influence of the type and position of the substituents on chiral recognition and enantioseparation abilities was studied in detail, and the structural dependence on enantioseparation performance was particularly demonstrated. It was found that methyl- and chloro-substituted chitosan bis(phenylcarbamate)-(N-hexanamide)s possessed comparable enantioseparation performances, whereas chloro-substituted chitosan bis(phenylcarbamate)-(N-cyclohexylformamide)s exhibited much more powerful chiral recognition and enantioseparation abilities than the methyl-substituted ones. Among all the prepared chiral selectors, those with the combination of the cyclohexyl group at the 2-position of the glucose skeleton in the chitosan derivatives and the chlorophenyl group at the 3-/6-positions seemed to be more preferable for enantiomeric separation. As a result, the chitosan bis(3,4-dichlorophenylcarbamate)-(N-cyclohexylformamide) possessed the best enantioseparation performance. The solvent tolerability of the prepared chiral selectors was also investigated in the present study. Compared with the classical coated-type chiral separation materials derived from cellulose/amylose derivatives, the N-cyclohexylcarbonyl and N-hexanoyl chitosans based chiral stationary phases were observed to possess more favorable solvent tolerability, thus possibly widening their applications for various practical enantioseparations.

High-performance chiral stationary phases based on chitosan derivatives with a branched-chain alkyl urea

In this study, two series of chitosan 3,6-bis(arylcarbamate)-2-(isobutylurea)s and corresponding coated-type chiral stationary phases (CSPs) were prepared from two kinds of chitosans with different molecular weights. Most of the prepared CSPs demonstrated better enantioseparation performance than the homemade CSP of cellulose tris(3,5-dimethylphenylcarbamate). The CSPs of chitosan 3,6-bis(4-methylphenylcarbamate)-2-(isobutylurea) with higher molecular weight and chitosan 3,6-bis(3-chloro-4-methylphenylcarbamate)-2-(isobutylurea) with lower molecular weight possessed outstanding chiral recognition abilities which were at least as good as that of the commercialized CSP of Chiralcel OD–H towards the tested chiral analytes. Except for the two CSPs derived from chitosan 3,6-bis(4-methylphenylcarbamate)-2-(isobutylurea)s, the CSPs (the first class) with the chiral selectors of lower molecular weight provided better enantioseparations than the ones (the second class) with the chiral selectors of higher molecular weight. On the other hand, the chiral selectors of the first class CSPs showed higher swelling capacities in organic solvents than the ones of the second class. All prepared CSPs could be analyzed with a wider range of mobile phases, in which some “unusual organic solvents” such as ethyl acetate, chloroform and THF etc. could be used as additives. According to separation performance and tolerance against organic solvents, we concluded that the chitosan derivatives with branched-chain alkyl urea at 2-C of glucosamine residue were preferable to be used as chiral selectors for enantiomeric separation.

Amylose Derivatives as Versatile Chiral Selectors for Enantiomeric Separation in High-Performance Liquid Chromatography and Capillary Electrophoresis

Amylose Derivatives as Versatile Chiral Selectors for Enantiomeric Separation in High-Performance Liquid Chromatography and Capillary Electrophoresis

Cationic cyclodextrin as versatile chiral selector for enantiomeric separation in capillary electrophoresis

A novel cationic cyclodextrin, mono-6A-(3-methoxypropan-1-ammonium)-6A-β-cyclodextrin chloride, has been developed and used as chiral selector in capillary electrophoresis (CE). This chiral selector has three recognition sites: β-CD, ammonium cation and methoxy group in the sidearm to contribute three corresponding driving forces including inclusion complexation, electrostatic interaction and hydrogen bonding. This elegantly designed CD exhibits outstanding enantioselectivities in CE for a wide range of acidic and ampholytic racemates due to the extra hydrogen bonding for the chiral recognition. Under optimum pH 6.0, chiral resolutions over 10 can be readily achieved for acidic racemates with CD concentration below 10mM. This cationic CD exhibits great potential for versatile chiral separation in CE. The finding in this study may be applied to construct new host–guest systems for practical applications.

Evaluation of clarithromycin lactobionate as a novel chiral selector for enantiomeric separation of basic drugs in capillary electrophoresis

Nowadays, macrocyclic antibiotics are presenting an increasing number of enantioseparation applications. The macrocyclic antibiotics used as chiral selectors in capillary electrophoresis (CE) include the ansamycins and the glycopeptides. The macrolides, another important class of macrocyclic antibiotics, have been reported as a new type of chiral selectors recently. In this study, clarithromycin lactobionate (CL), belonging to the group of macrolide antibiotics, was first investigated for its potential as a novel chiral selector in CE for enantiomeric separation of several basic drugs. As observed, CL allowed excellent separation of the enantiomers of metoprolol, atenolol, propranolol, bisoprolol, esmolol, ritodrine, and amlodipine, as well as partial enantioresolution of labetalol and nefopam. In addition, CL possesses advantages such as high solubility and low viscosity in the solvent and very weak UV absorption. In the course of this study, it was found that both migration times and enantioseparation of the basic drugs were influenced by several experimental parameters, e.g. selector concentration, the composition and pH of the BGE, the type and concentration of organic modifier, and applied voltage. Thus, the effects of these factors were systematically investigated, and satisfactory enantioseparations of the studied drugs were achieved at the buffer pH range of 7.3-7.5 using 12.5 mM borax buffer with 50% v/v methanol, 60 mM CL, and 20 kV applied voltage. Moreover, comparison of the influences of the studied parameters was further investigated by means of Statistical Product and Service Solutions (SPSS) in this article.

Dodecyl thioglycopyranoside sulfates: Novel sugar‐based surfactants for enantiomeric separations by micellar electrokinetic capillary chromatography

Four novel chiral anionic surfactants having carbohydrate hydrophilic heads, sodium n-dodecyl 1-thio-beta-D-glucopyranoside 6-hydrogen sulfate (6-betaGlcD), sodium n-dodecyl 1-thio-beta-L-glucopyranoside 6-hydrogen sulfate (6-betaGlcL), sodium n-dodecyl 1-thio-beta-L-fucopyranoside 3-hydrogen sulfate (3-betaFucL), and sodium n-dodecyl 1-thio-alpha-L-rhamnopyranoside 3-hydrogen sulfate (3-alphaRhaL), were synthesized by selective sulfation of the corresponding thioglycosides. Their CMC determined by fluorescence using pyrene as a probe in water was 1.3-2.7 mM. These surfactants found to be useful as chiral selectors for enantiomeric separation by MEKC. The enantiomeric separation was optimized with respect to pH, buffer concentration, and surfactant concentration. Under the optimized conditions (50 mM phosphate buffer at pH 6.5, 30 mM surfactant, 20 kV), the enantiomeric separations of five dansylated amino acids (Dns-AAs) were achieved within approximately 20 min with the migration order of Val<Met<Leu<Phe<Trp. With 6-betaGlcD, all D-forms of Dns-AAs were found to migrate faster than the corresponding L-forms, whereas the migration order of the enantiomers was completely reversed with the surfactant 6-betaGlcL having inversed absolute configuration of 6-betaGlcD. Among four surfactants examined, beta-anomers were much superior chiral selectors than alpha-anomers, and the maximum resolution was obtained with the 6-deoxy sugar, 3-betaFucL. These results indicated that the structures of the surfactant head groups including their anomeric configurations have significant effects on the enantiomeric separation and the migration behavior in MEKC.

Evaluation of carbon nanostructures as chiral selectors for direct enantiomeric separation of ephedrines by EKC

Single-walled nanotubes and multi-walled nanotubes (MWNTs) have been evaluated as chiral selectors for the enantiomeric separation of ephedrines by using EKC with surfactant-coated carbon nanotubes. The analysed compounds were (+/-)-ephedrine, (+/-)-norephedrine and (+/-)-N-methylephedrine. The potential of those carbon nanostructures as chiral selectors has been evaluated by changing different experimental variables such as pH, addition of organic modifiers, potential and injection time. The capability of MWNTs to resolve enantiomeric mixtures was demonstrated by using partial filling of the capillary with concentrated surfactant-coated MWNTs. Differences in the enantioselectivity were discussed.

Capillary zone electrophoretic chiral discrimination using 6‐O‐(2‐hydroxy‐3‐trimethylammoniopropyl)‐β‐cyclodextrin as a chiral selector

A charged highly water-soluble CD derivative, 6-O-(2-hydroxy-3-trimethylammoniopropyl)-beta-CD (herein noted as 6-HPTMA-beta-CD) was synthesized and successfully used as a chiral selector for enantiomeric separation of some acidic compounds by CZE in an uncoated capillary. Substitution with 2-hydroxy-3-trimethylammoniopropyl groups at the primary hydroxyl group of the CD was aimed at influencing the magnitude and selectivity of analyte-CD interactions. The behavior of 6-HPTMA-beta-CD was compared with that of the commercially available quaternary ammonium-beta-CD (QA-beta-CD) under the same separating conditions. The experiments were carried out using a BGE consisting of 50 mM phosphate in the pH range of 4-6 by adding a relatively low concentration of chiral selector (less than 10 mM). The effects of the concentration of CD and the pH of the electrolyte on the resolution of these compounds were studied.

Enantiomeric separations of some acidic compounds with cationic cyclodextrin by capillary electrophoresis

A new charged highly water soluble cyclodextrin (CD) derivative, 2- O-(2-aminoethyl-imino-propyl)-β- O-hydroxypropyl-β-CD (2-AIPHP-C-CD) was synthesized and successfully used as a chiral selector for enantiomeric separation of some acidic compounds. In capillary zone electrophoresis in a polyacrylamide coated capillary, these enantiomer separations were compared with the results using β-CD and two neutral CD derivatives. Substitution with 2- O-(2-aminoethyl-imino-propyl)-2- O-hydroxypropyl at the secondary hydroxyl sites of the CD is aimed at influencing the magnitude and selectivity of analyte–CD interactions. The effects of the type of CD, the pH of the electrolyte and the shape of acidic compounds on the migration time and resolution were studied.

Comparing cyclodextrin derivatives as chiral selectors for enantiomeric separation in capillary electrophoresis

A total of 26 different cyclodextrin (CD) derivatives with different functional groups and degrees of substitution were tested against 35 basic pharmaceutical compounds in an effort to investigate their effectiveness as chiral selectors for enantiomeric separation in capillary electrophoresis (CE). Testing was performed under the same conditions using a low pH buffer (25 m M phosphate buffer at pH∼2.5). Five CD derivatives, namely, highly sulfated-β-CD, highly sulfated-α-CD, hydroxypropyl-β-CD (degree of substitution∼1), heptakis-(2,6- O-dimethyl)-β-CD, and heptakis(2,3,6- O-trimethyl)-β-CD were identified to be most effective for enantiomeric separations and have a wide range of enantiomeric selectivity towards the model compounds. Over 90% of the model compounds were enantiomerically resolved with the five identified CD derivatives, at a minimum resolution of 0.5. An additional 20 compounds were also tested to demonstrate the validity of the identified CD derivatives. The five CD derivatives were recommended as the starting chiral selectors in developing enantiomeric separation methods by CE.

Cationic β-cyclodextrin derivative for chiral separations

A novel hepta-substituted β-cyclodextrin bearing the methoxyethylamine group linked to the upper cyclodextrin rim was successfully used as a chiral selector for enantiomeric separation of non-steroidal anti-inflammatory drugs (NSAIDs) and phenoxypropionic acid herbicides (PPAHs). Separation parameters such as pH and concentration were found to have major influences on enantiomeric resolution of the NSAIDs and PPAHs. Results indicate that heptakis(6-methoxyethylamine-6-deoxy)-β-cyclodextrin [β-CD-OMe (VII)] performs exceptionally well for the enantiomeric resolution of NSAIDs: indoprofen and fenoprofen ( R s=11 and 14, respectively). In addition, baseline enantiomeric separation of a mixture of six pairs of PPAHs was achieved in under 30 min. Compared to other cationic β-cyclodextrins reported in the literature, the β-CD-OMe (VII) showed improved selectivity for both classes of the aforementioned anionic racemates.

Ruggedness of enantiomeric separation by capillary electrophoresis and high-performance liquid chromatography with methylated cyclodextrins as chiral selectors

When applying cyclodextrin (CD) derivatives as chiral selectors for enantiomeric separation in different separation methods, the difference in degree of substitution (DS) and substitution pattern of the CD derivative may lead to complications. Seven different methylated β-cyclodextrin derivatives were tested as additives in the background electrolyte in capillary electrophoresis (CE) and as an additive to the mobile phase in high-performance liquid chromatography (HPLC). The substitution patterns of heptakis(2,6-di-O-methyl)-β-CD (DIMEB) and randomly methylated β-CD samples were compared using a simple thin-layer chromatography method. The CE method was sensitive to the quality of the chiral selector and it was solute dependent. While the enantiomeric separation of N-methylephedrine and terbutaline was excellent with all DIMEBs, in the case of hexobarbital, the separation failed with one DIMEB sample. The HPLC method was less sensitive to the quality of the chiral selector than the CE method.

Evaluation of 2-Chrysenyl and 1-Pyrenyltartramide Derivatives as Chiral Selectors for Enantiomeric Separation on Porous Graphitic Carbon High-performance Liquid Chromatographic Columns

Four chiral stationary phases were proposed containing (R,R)-N,N′-isopropyltartramide and (R,R)-N,N′-(3-nitrophenyl)tartramide groups covalently linked to 2-chrysene and 1-pyrene. They were strongly adsorbed on porous graphitic carbon to afford carbon-based chiral stationary phases. The stereoselective properties of these phases were evaluated using high-performance liquid chromatography and the phases were found to be capable of the recognition of aromatic alcohols, binaphthyl analogues, β-blocking agents and anti-inflammatory agents. The addition of ammonium acetate to the mobile phase enhanced the enantioselectivity for some solutes. The influences of the solute structure and the chiral selector structure on chiral recognition were examined. The effect of substituents attached to the tartramide selectors, such as hydroxyl, acetyl and/or nitrobenzene groups, was studied. A low column temperature improved the enantioselective resolution. The stability of the adsorbed stationary phases under the chromatographic conditions (using polar and non-polar solvents) was also investigated.

ChemInform Abstract: Synthesis of 17H‐Tetrabenzo(a,c,g,i)fluorene Derivatives as Chiral Selectors for Enantiomeric Separation by HPLC on Porous Graphitized Carbon.

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Synthesis of 17H-tetrabenzo[a,c,g,i]fluorene derivatives as chiral selectors for enantiomeric separation by HPLC on porous graphitised carbon

The synthesis of the amides 2 which are designed to be selectors containing the chiral N-(3,5-dinitrobenzoyl)-α-phenylglycine covalently linked to tetrabenzo[a,c,g,i]fluorene is described. These amides are strongly adsorbed onto porous graphitised carbon, which affords chiral stationary phases that are able to resolve both racemic aromatic alcohols 3 and the methyl esters of Fmoc amino acids 4 on microgram quantities using high-pressure liquid chromatography. Two methods of preparation of these chiral phases from 2 and porous graphitised carbon are described and the stability of these phases to the chromatographic conditions and to water have also been investigated.