Combination of cyclodextrins and polymeric surfactants for chiral separations

A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) method was applied to the enantioseparation of three binaphthyl derivatives using neutral CDs (i.e., beta- and gamma-CD) in combination with various chiral amino acid-based polymeric surfactants (PSs). Both the D- and L-configurations of poly(sodium N-undecanoyl alaninate), poly(sodium N-undecanoyl leucinate), and poly(sodium N-undecanoyl valinate) (poly(L-SUV)) were synthesized. The retention behavior of the three binaphthyl derivatives under optimum electrophoretic conditions using a single chiral additive (PS or CD) is discussed. In addition, the effect of CD cavity size and stereochemical configuration of polymeric surfactants on selectivity (alpha) and resolution (Rs) was investigated. The enantioseparation of (+/-)1,1'-binaphthyl-2,2'-diamine gave a reversal of enantiomeric order when using beta-CD in combination with any of the three D-configuration PS. However, better enantioseparation is obtained when using the corresponding L-configuration PS with beta-CD. A reversal of migration order (RMO) for the enantiomers of (+/-)1,1'-bi-2-naphthol was observed upon the addition of 10 mM gamma-CD to poly(L-SUV). However, no RMO of (+/-)1,1'-bi-2-naphthol was seen when either beta-CD or gamma-CD was combined with D-PS. The enantiomers of (+/-)1,1'-binaphthyl-2,2'-diyl hydrogen phosphate showed little enantioselective behavior toward the PS alone. However, combined D- or L-PS and beta-CD or gamma-CD systems gave increased Rs and alpha values. The chiral recognition of binaphthyl derivatives observed resulting from the various combinations of two chiral selectors is discussed.     

pH-dependent cyclodextrin capillary electrophoresis resolution of atropisomers

Five noncommercial and four commercially available cyclodextrin (CD) derivatives were tested as chiral auxiliaries for the capillary electrophoretic (CE) resolution of racemic 1,1'-bi-(2-naphthol) (BN), 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (BNHP), and 1,1'-binaphthyl-2,2'-diamine (BNA) at pH 4.0, 6.5, and 8.6. The noncommercial CDs were ethyloxycarbonyl-gamma-CD (ethylcarbonate-gamma-CD), dimethylamino ethyloxycarbonyl-beta-CD, a mercaptosuccinic acid derivative of beta-CD, a maleic acid derivative of beta-CD and heptakis(6-deoxy-6-amino)-beta-CD derivative with one amino group on the C-6 carbon of each glucose unit. Except for the latter, the remaining derivatives were synthesized for this work. Also commercially available methyl-beta-CD, hydroxypropyl-beta-CD and the native beta- and gamma-CDs were examined. Among the nine CDs tested, the maleic acid derivative of beta-CD gave the most interesting performances, since it resolved the atropisomers of BNA and BNHP in the same electrophoretic run at pH 4.0. It resolved the BNA racemate also at pH 6.5. Both the negatively charged CD tested were found to resolve anionic BNHP enantiomers, while positively charged CDs did not with cationic BNA. Several of the CDs investigated in this work were found to resolve the BNHP racemate, although at nonoptimal concentration. None of the experimented CDs was found to resolve the electrically neutral BN atropisomers pair at the three pHs considered, while some among these nine, experimented in a previous work, did so at higher pH.     

Comparison of monomeric and polymeric amino acid based surfactants for chiral separations

To better understand chiral recognition with polymeric amino acid based surfactants, the chromatographic performance of 18 monomeric and polymeric surfactants were compared for chiral analytes with various charge states and hydrophobicities. In this study, four amino acids (glycine, L-alanine, L-valine, and L-leucine) were chosen, and all possible combinations of the chiral single amino acid and dipeptide surfactants were synthesized. The results indicate that polymeric surfactants usually provide better chiral resolution for enantiomers of lorazepam, temazepam, 1,1'-bi-2-naphthol, and propranolol as compared to monomeric surfactants. In contrast, monomers perform better for chiral recognition of the 1,1'-bi-2-naphthyl-2,2'-diyl hydrogenphosphate enantiomers.     

Efficient resolution of racemic 1,1'-bi-2-naphthol with chiral selectors identified from a small library

Efficient resolution of racemic 1,1'-bi-2-naphthol, a well-studied analyte in chiral separation, was achieved using selectors developed from a small library. Separation factors (up to 7.2) obtained are significantly higher than the ones reported previously for this analyte. The library consists of 121 members and it does not contain the pi deficient 3,5-dinitrobenzoyl (Dnb) group. These highly efficient stationary phases may lead to the practical large-scale chromatographic resolution of enantiomers of 1,1'-bi-2-naphthol, which are widely used as chiral auxiliaries and ligands in asymmetric synthesis.     

A giant vesicle forming single tailed chiral surfactant for enantioseparation by micellar electrokinetic chromatography

Light microscopy has shown the existence of giant bilayer vesicles in aqueous solutions of a novel chiral surfactant, sodium N-[4-dodecyloxybenzoyl]-L-valinate, which acts as a very good chiral selector for enantioseparation of (+/-)-1,1'-bi-2-naphthol and (+/-)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate by micellar electrokinetic chromatography.     

七-(2,6-二-O-甲基)-β-环糊精对1,1'-联萘酚对映体手性识别的电喷雾质谱研究

利用电喷雾质谱研究了β-环糊精、七-(2,6-二-O-甲基)-β-环糊精作为手性识别试剂对1,1'-联萘酚对映体的手性识别效应. 实验结果表明, 在气相中, β-环糊精与七-(2,6-二-O-甲基)-β-环糊精都可以与联萘酚形成非共价复合物. 对形成的复合物的串联质谱研究表明, β-环糊精不能识别联萘酚对映体, 而七-(2,6-二-O-甲基)-β-环糊精对联萘酚对映体有较强的手性识别效应. 进一步研究表明七-(2,6-二-O-甲基)-β-环糊精与联萘酚对映体混合比例以及CID能量对于手性识别并无影响.     

Enantiomeric separations of binaphthyl derivatives by capillary electrophoresis using N-(2-hydroxydodecyl)-L-threonine as chiral selector: effect of organic additives

The chiral selectivity of a novel amphiphile, N-(2-hydroxydodecyl)-L-threonine (2-HDT), was evaluated for enantiomeric resolution of three binaphthyl derivatives (+/-)-1,1'-bi-2-naphthol, (+/-)-1,1'-binaphthyl-2,2'-diamine, and (+/-)-1,1'-binaphthyl-2,2'-diylhdrogen phosphate (BNP) by micellar EKC. The effects of three organic modifiers, methanol, isopropanol, and acetonitrile, on the separations of enantiomers of these compounds were investigated. Separation of enantiomers could be achieved in relatively dilute solutions of the pure surfactant. However, best separations of enantiomers were obtained only in the presence of 10% v/v acetonitrile. Enantiomeric impurity in nonracemic mixtures of R- and S-forms of BNP was determined.     

Studies of the resolution of racemic 1,1'-bi-2-naphthol with a dipeptide chiral selector identified from a small library

Several new stationary phases were prepared to study the structure-activity relationship of the chiral resolution of racemic 1,1'-bi-2-naphthol with a modified dipeptide Asn-Asn selector. The number of amino acid, the side chain protecting groups of the amino acid, and the Fmoc end-capping group all proved important for enantioselectivity. The linker also influenced enantioselectivity. Influence of the length of the linker appears to be related to the accessibility of chiral selectors. The bond through which the selector is attached to the linker proved important. Based on these results, it is postulated that hydrogen bonding interactions between one side chain amide group of one Asn and the oxygen on the backbone of another Asn with the two hydroxyl groups of the analyte play an important role in the resolution of racemic 1,1'-bi-2-naphthol with the modified dipeptide Asn-Asn selector.     

Use of poly(sodium oleyl-L-leucylvalinate) surfactant for the separation of chiral compounds in micellar electrokinetic chromatography

A chiral amino acid-based monomeric and polymeric surfactant, sodium oleyl-L-leucylvalinate) (L-SOLV) and poly(sodium oleyl-L-leucylvalinate) (poly-L-SOLV) were synthesized and used for chiral separations in micellar electrokinetic chromatography (MEKC). Poly-L-SOLV was used successfully in the separation of various enantiomers of neutral, acidic, and basic analytes such as 1,1'-bi-2-napthol, 1,1'-binaphthyl-2,2'-diamine, benzoin, hydrobenzoin, benzoin methylether, warfarin, and coumachlor obtaining well-resolved peaks but with only partial separation of temazepam. In addition, the atropisomer 1,1'-binaphthyl-2, 2'-dihydrogen phosphate was chosen to study the applicability of the polymeric surfactant over a wide range of parameters such as concentration, temperature, voltage, and pH. The most striking characteristic of this new surfactant is its high hydrophobicity. It is favorable to interactions with hydrophobic chiral analytes, and thus may provide better chiral recognition for the compounds.     

Separation of binaphthyl enantiomers by capillary zone electrophoresis and electrokinetic chromatography

The capillary electrophoretic (CE) separation of the enantiomers of three binaphthyl compounds is investigated. Several CE modes such as cyclodextrin (CD) modified capillary zone electrophoresis (CZE) (CD-CZE), micellar electrokinetic chromatography (MEKC), cyclodextrin electrokinetic chromatography (CD-EKC), etc. are employed for the simultaneous enantiomer separation of the three solutes. The successful separation was achieved by combining two modes, in other words by using more than two chiral selectors. A development of the CE enantiomer separation is demonstrated for the binaphthyl compounds. The enantioselectivity of binaphthyl compounds is alo briefly discussed.     

Chiral recognition of binaphthyl derivatives using electrokinetic chromatography and steady-state fluorescence anisotropy: effect of temperature

The effect of temperature on the chiral recognition of binaphthyl derivatives in the presence of poly sodium N-undecanoyl-LL-leucyl-leucinate (poly LL-SULL) is examined using electrokinetic chromatography (EKC) and steady-state fluorescence anisotropy. An examination of the effect of temperature suggests that the chiral recognition of 1,1'-binaphthyl-2,2'-diol enantiomers improves with increasing temperature, whereas lower temperatures resulted in better enantiosolectivity in the case of 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate enantiomers. In addition, steady-state fluorescence anisotropy results show that the anisotropy of the two enantiomers are different when complexed to poly-(LL) SULL. As would be expected, the enantiomer that binds stronger to the chiral pseudostationary phase, as evidenced by EKC experiments, had higher anisotropy values. The results of this study suggest that steady-state fluorescence anisotropy can be used to gain further insight into chiral recognition.     

Equilibrium binding model of bile salt-mediated chiral micellar electrokinetic capillary chromatography.

Optimum concentration of bile salts in chiral separations depends on both the aggregation properties of the surfactant and the stability of the analyte-micelle complexes. An equilibrium model is proposed in which these two effects are treated separately. First the aggregation constants should be determined under the experimental conditions of the chiral MEKC analysis. With these data, the equilibrium concentrations of bile salt aggregates can be calculated at any total surfactant concentration. Using the Offord equation to approximate the mobilities of the enantiomer-bile salt complexes, a model function has been derived to fit the experimental mobilities. The method yields the binding constants of the enantiomers to each aggregate present. Those species are assumed to be important in the chiral recognition process, which have significantly different stability constants for the enantiomers. The method is demonstrated by the chiral separation of R- and S-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate with sodium taurodeoxycholate. Based on the calculated binding constants, tetrameric aggregates are assumed to be the discriminating species, while no significant difference in enantiomer binding to dimers was found.     

Enantioseparation of four cis and trans diastereomers of 2',3'-didehydro-2',3'-dideoxythymidine analogs, by high-performance liquid chromatography and capillary electrophoresis

Compounds 1-4 are the four stereoisomers of a synthetic new potential antiviral agent (d4T analog) containing two chiral centers and a base (uracil). Both high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) techniques were used to separate and quantify enantiomers with high resolution. The determination of enantiomeric purity of the compounds was developed using both amylose chiral stationary phase by HPLC and anionic cyclodextrins (highly S-CD) as chiral selectors in CE. The HPLC method was found to be superior in sensitivity to the CE method.     

Cation‐enhanced capillary electrophoresis separation of atropoisomer anions

CE was used to study the separation of the atropoisomers of four phosphoric acids and two sulfonic acids and the enantiomers of two phosphoric acids. All solutes are in their anionic forms in aqueous electrolytes. The chiral additives were two hydroxypropyl cyclodextrins (CDs) and cyclofructan 6 (CF6). The CDs were able to separate four solutes and the CF6 additive could separate only one: 1,1′‐binaphthyl‐2,2′‐diyl hydrogenphosphate (BHP). Since CF6 is able to bind with cations, nitrate of alkaline metals, Ba²⁺, and Pb²⁺ were added, greatly improving the BHP separation at the expense of longer migration times. There seems to be a link between CF6–cation‐binding constants and BHP resolution factors. Cation additions were also performed with CD selectors that are less prone to form complexes with cations. Significant improvements of enantiomer or atropoisomer separations were observed also associated with longer migration times. It is speculated that the anionic solutes associate with the added cations forming larger entities better differentiated by CDs.     

Enantiomeric separation of a group of chiral dihydropyridines by electrokinetic chromatography

Electrokinetic chromatography (EKC) was employed to achieve the enantiomeric separation of a group of chiral 1,4-dihydropyridines (DHPs) with pharmacological activity. Micelles of bile salts alone or mixed with neutral cyclodextrins, micelles of sodium dodecyl sulfate (SDS) mixed with neutral cyclodextrins, and anionic cyclodextrin derivatives, i.e., carboxymethyl-gamma-cyclodextrin (CM-gamma-CD), carboxymethyl-beta-cyclodextrin (CM-beta-CD), and succinylated beta-cyclodextrin (Succ-beta-CD), were employed as pseudostationary phases. The enantiomeric separation ability of these chiral selectors with respect to DHPs was studied in different experimental conditions. CM-beta-CD was shown to be the best chiral selector to perform the enantiomeric separation of DHPs by EKC. Next, the influence of the CM-beta-CD concentration, the pH and nature of the buffer, the temperature, and the applied voltage on the enantiomeric resolution of DHPs was studied. The use of a 50 mM ammonium acetate buffer, pH 6.7, 25 mM in CM-beta-CD together with an applied voltage of 15 or 20 kV, and a temperature of 15 degrees C enabled the individual enantiomeric separation of twelve DHPs, each one into its two enantiomers, and their separation in multicomponent mixtures of up to six DHPs into all their enantiomers.     

1，1’—联—2—萘酚在不对称催化中的应用新进展

光学活性的1，1’—联—2—萘酚(BINOL)及其衍生物作为优异的手性配体应用 于不对称催化中已取得了巨大进展，显示出广阔的应用前景．对BINOL小分子和高 分子在各种不对称催化反应中的最新进展和发展方向进行了评述，并介绍了有关 BINOL的几种新型催化策略．     

Use of NMR binding interaction mapping techniques to examine interactions of chiral molecules with molecular micelles

NMR spectroscopy was used to investigate the association of four chiral molecules with the molecular micelle poly(sodium N-undecanoyl-l-leucylvalinate) (poly(SULV)). Adding poly(SULV) to the background electrolyte in electrokinetic chromatography (EKC) allows enantiomeric resolution to be achieved because enantiomers interact differentially with the chiral centers on the micelle headgroups as they both move in the electric field. Pulsed field gradient diffusion experiments were used to measure molecular micelle association constants for enantiomers of each analyte. These association constants were consistent with EKC elution order for the compounds 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BNP), 1,1'-bi-2-naphthol (BOH), and Troger's base. In addition, nuclear Overhauser enhancement spectroscopy, nuclear Overhauser effect difference, and intermolecular cross relaxation diffusion experiments were used to generate binding interaction maps for each chiral analyte. These maps showed that BNP and BOH inserted into the surfactant headgroup's major chiral groove and interacted predominately with the leucine chiral center. (+)-Troger's base was also found to insert into the major chiral groove. However, this compound instead interacted with the valine chiral atom. In diffusion experiments with long diffusion times, the linearized diffusion plots for each analyte-molecular micelle mixture showed curvature characteristic of intermolecular cross relaxation. The magnitude of this effect scaled linearly with the analytes' free energies of binding.     

Chiral Separations of Five Organic Catalysts by Cyclodextrin-modified Capillary Zone Electrophoresis

Chiral separation is very important and become a significant task of analytical chemistry in many fields. Capillary electrophoresis (CE) is a technique undergoing rapid development for chiral separation at the present time. With its high efficiency, simple operation, and extremely small sample volume,CE has become a powerful tool for chiral separation. There are many chiral selectors, such as cyclodextrins (CDs), proteins, chiral surfactants, antibiotics, bile salts, using in CE chiral separation. CDs has been most wildly used in them. Cyclodextrin (CD) is a cyclic sugar made of certain glucose units in which each has 5 chiral centers and it shows the shape of cavity with a big end and a small end. The inside of CD is hydrophobic and the outside is hydrophilic. The chiral selectivity of CD comes from the formation of host-guest compound between CD and analytes. The differences of the hydrogen-bond and the other interactions between CD and two enantiomers cause enantio-selectivity.     

Resolution of the enantiomers of oxamniquine by capillary electrophoresis and high-performance liquid chromatography with cyclodextrins and heparin as chiral selectors

The methods of separation of the enantiomers of the chiral drug oxamniquine are compared, between HPLC with either cyclodextrins and their related derivatives as chiral selectors in the mobile phase or immobilisedin a chiral stationary phase (as Cyclobond I and II) and between capillary zone electrophoresis (CZE) where the cyclodextrins are added to the buffer solution. The HPLC experiments, which included structured method optimisation were largely unsuccessful in resolving the enantiomers, with the exception of when a Chiral-AGP protein stationary phase was introduced into the programme. However although this chiral stationary phase provided baseline resolution of the enantiomers the stability of the method was suspect to small changes in the pH (0.2 units). In contrast the CZE method developed for both cyclodextrins and their derivatives gave good resolution of the enantiomers and method stability (R.S.D. <1%, N = 10 on precision). The basis of the interaction mechanism between selector and selectand was shown as a 1:2 relationship of cyclodextrin to analyte by NMR. In addition the polysaccharide, heparin was investigated as a chiral additive and excellent resolution of the oxaminiquine was achieved with 3 mM heparin in 50 mM sodium dihydrogenphosphate (pH 3.0) as buffer in CZE, which also gave a stable procedure. This method allowed the detection of each of the enantiomers in the presence of the other down to 0.23% (m/m). The overall composition of the heparin material from different sources can however be slightly variable and this can result in small differences in resolution capability.     

Enantiopurity analysis of new types of acyclic nucleoside phosphonates by capillary electrophoresis with cyclodextrins as chiral selectors

CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3‐hydroxypropan‐2‐yl)‐1H‐1,2,3‐triazol‐4‐yl]phosphonic acid, 2‐[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2?(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6‐diaminopurine, uracil, and 5‐bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with a 2‐(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51–2.94, within a reasonable time, 13–28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β‐cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with 2‐(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β‐cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.