Cyclodextrin-assisted capillary electrophoretic resolution of 1,1'-bi-2-naphthol atropisomers.

Native beta- and gamma-cyclodextrin (CD), neutral beta-CD derivatives and ethylcarbonate derivatives of beta- and gamma-CD were used as stereoselective additives for CD-capillary zone electrophoresis (CZE) resolution of atropisomers of 1,1'-bi-(2-naphthol) (BN). CZE experiments at variable CD concentration allowed calculating binding constants from electrophoretic mobility data, corrected for electroosmotic flow (EOF) and running buffer viscosity variations. The CDs were chosen on the basis of geometric examination of molecular models of BN and CDs that suggested the possibility of inclusion complexes formation. Optimum concentrations, with aqueous 25 mM phosphate running buffer at pH 10.5, 36 cm x 50 microm capillary and 10 kV applied potential, were 3.6, 3.9, 2.1, 2.2, 1.9 mM for beta-CD, gamma-CD, ethylcarbonate-beta-CD, methyl-beta-CD and hydroxypropyl-beta-CD, respectively.     

Polymeric alkenoxy amino acid surfactants: III. Chiral separations of binaphthyl derivatives

Micellar electrokinetic chromatography (MEKC) was investigated for the enantiomeric separations of three binaphthyl derivatives ((+/-)-1,1'-bi-(2-naphthol) (BOH), (+/-)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (BNP), and (+/-)-1,1'-binaphthyl-2,2'-diamine (BNA)) using two recently synthesized chiral polymeric surfactants (polysodium N-undecenoxy carbonyl-L-leucinate (poly-L-SUCL) and polysodium N-undecenoxy carbonyl-L-isoleucinate (poly-L-SUCIL)) in our laboratory. Enantiomeric separation (resolution and selectivity) of the binaphthyl derivatives was influenced by polymerization concentration of the monomeric surfactant, pH, type and concentration of the background electrolyte (BGE) as well as concentration of the polymeric surfactant. Two BGEs (dibasic phosphate and Tris-borate) were compared for this study. The use of dibasic phosphate as BGE in poly-L-SUCL provides baseline resolution of (+/-) BOH and (+/-) BNP, however, no resolution and selectivity at all was observed for (+/-) BNA. A similar approach was adopted with Tris-borate-poly-L-SUCL system at fixed pH 10.1, which resulted in baseline resolution of all three binaphthyl derivatives. Although R(s) of binaphthyl derivatives was always higher and electroosmotic flow (EOF) was always lower using Tris-borate than with dibasic phosphate, the selectivity values for the two buffer systems did not differ significantly. In addition, it was found that poly-L-SUCL provided better enantiomeric resolution and selectivity for (+/-) BOH and (+/-) BNA, while poly-L-SUCIL provided enhanced enantiomeric resolution but similar enantioselectivity for (+/-) BNP. This indicates that the depth of analyte penetration into the palisade layer and the micellar core are responsible for chiral recognition of hydrophobic analyte (e.g., (+/-) BOH, and (+/-) BNA) whereas for moderately hydrophobic analyte (e.g., (+/-) BNP) interaction with the polar head group seems to dictate chiral recognition. Simultaneous enantioresolution of all three binaphthyl derivatives was possible in a single electrophoretic run using either poly-L-SUCL or poly-L-SUCIL. Further comparison of the two polymeric surfactants showed that poly-L-SUCL provided slightly longer analysis time than poly-L-SUCIL but the use of the former polymeric surfactant should be preferred due to its ability to provide complete baseline resolution and higher selectivity of all the three atropisomers with a wider chiral window.     

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.     

Mechanism of molecular recognition on molecular imprinted monolith by capillary electrochromatography

The recognition mechanism of molecularly imprinted polymer (MIP) in capillary electrochromatography (CEC) is complicated since it possesses a hybrid process, which comprises the features of chromatographic retention, electrophoretic migration and molecular imprinting. For an understanding of the molecular recognition of MIP in CEC, a monolithic MIP in a capillary with 1,1'-binaphthyl-2,2'-diamine (BNA) imprinting was prepared by in situ copolymerization of imprinted molecule, methacrylic acid and ethylene glycol dimethacrylate in porogenic solvent, a mixture of toluene-isooctane. Strong recognition ability and high column performance (theory plates was 43,000 plates/m) of BNA were achieved on this monolithic MIP in CEC mode. In addition, BNA and its structural analogue, 1,1'-bi-2, 2'-naphthol, differing in functional groups, were used as model compounds to study imprinting effect on the resultant BNA-imprinted monolithic column, a reference column without imprinting of BNA and a open capillary. The effects of organic modifier concentration, pH value of buffer, salt concentration of buffer and column temperature on the retention and recognition of two compounds were investigated. The results showed that the molecular recognition on MIP monolith in CEC mode mainly derived from imprinting cavities on BNA-imprinted polymer other than chromatographic retention and electrophoretic migration.     

Enantioseparation of binaphthol and its mono derivatives by cyclodextrin-modified capillary zone electrophoresis

Chiral binaphthols belong to the group of most effective ligands for asymmetrical catalysis. In this context, various binaphthols presenting original substituents have been synthesized. Their study through capillary electrophoresis is the object of this work. The literature dedicated to the separation of atropisomers by capillary electrophoresis, corresponding only to binaphthol, reveals that its enantioseparation is always delicate because of the influence of many factors and the resolutions obtained are weak. Therefore, for a structured optimization, we first successfully evaluated the acidity constants of different binaphthols by means of capillary electrophoresis. With these known physicochemical characteristics, we could successfully carry out enantiomeric separations of the different binaphthols at pH 11.5, practically in completely ionized form, in phosphate medium, and in the presence of cyclodextrin (CD), with analysis times lower than 8min. The nature of CDs (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD), HP-beta-CD, HP-gamma-CD and trimethyl-beta-CD (TM-beta-CD)) and other factors in relation to enantiomeric resolution (applied voltage, nature and concentration of the electrolyte, and concentration of cyclodextrin) were optimized. These studies allowed us to determine the optimal conditions of separation (concentration and nature of CD) for each of the studied binaphthols. It is necessary to mention that, for the 1,1'-binaphthyl-2,2'-diol (Binol) at pH 11.5, the S atropisomer always migrated first, regardless of the nature and concentration of the cyclodextrin used. Moreover, an inversion in elution order of the two atropisomers as a function of pH was observed with gamma-CD (pH range: 10-11.5). The R atropisomer migrated first at pH 10. At pH 10.8 the migration order of the two atropisomers of Binol was reversed as a function of gamma-CD concentration. Finally, the addition of chiral ionic liquids (R(-)-1-hydroxy-N,N,N-trimethylbutan-2-aminium bis(trifluoromethylsulfonyl)imide and S(+)-tetrabutylammonium camphorsulfonate) was conducted. In the case of S(+)-tetrabutylammonium camphorsulfonate, a weak antagonistic effect was observed with modeling the evolution of enantiomeric resolution by means of the experimental design, while in the case of R(-)-1-hydroxy-N,N,N-trimethylbutan-2-aminium bis(trifluoromethylsulfonyl)imide the effect was neutral.     

Embedding an allylmetal dimer in a chiral cavity: the unprecedented stereoselectivity of a twofold wittig [1,2]-rearrangement

After alpha,alpha'-dimetalation, both 2,2'-diallyloxy-1,1'-binaphthyl and 2,2'-di-2-methylallyloxy-1,1'-binaphthyl undergo the Wittig rearrangement with perfect diastereoselectivity. When racemic 1,1'-binaphthyl-2,2'-diol ("BINOL") is used as the starting material, it gives rise to a 1:1 mixture of antipodal stereoisomers, whereas enantiomerically pure (M)-2,2'-diallyloxy-1,1'-binaphthyl affords (M)-(S,S)-1,1-(1,1'-binaphthyl-2,2'-diyl)bis(2-propen-1-ol) as the sole product. The (M)-(S,S)/(P)-(R,R) mixture resulting from the rearrangement of racemic 2,2'-diallyloxy-1,1'-binaphthyl can be effectively subjected to a kinetic racemate resolution by applying the Sharpless-Katsuki asymmetric epoxidation. The single-sided Wittig rearrangement of 2-allyloxy-2'-propyloxy-1,1'-binaphthyl proceeds without any diastereoselectivity as this substrate can only be monometalated and hence is incapable of intramolecular aggregate formation which is instrumental for the observed stereoselectivity.     

Retention behaviour of peptides in capillary electrochromatography using an embedded ammonium in dodecacyl stationary phase

A highly water-soluble new cyclodextrin (CD) derivative 2-O-acetonyl-2-O-hydroxypropyl-beta-CD (2-AHP-beta-CD) was synthesized and tested as an effective chiral selector for the capillary zone electrophoretic resolution (Rs) of several basic and acidic analytes. The primary purpose of the research was to explore the capability of the 2-AHP-beta-CD as chiral selectors on comparison with the neutral CDs such as beta-CD, DM-beta-CD and HP-beta-CD. Substitution with 2-O-acetonyl-2-O-hydroxypropyl group at the secondary hydroxyl sites of the CD is aimed at influencing the magnitude and selectivity of analyte-CD interactions. The chiral resolution was strongly influenced by the concentration of the CDs and buffer pH. 2-AHP-beta-CD showed the best enantiomer resolution properties among the tested compounds, while the other CDs showed inferior or no performances at all.     

Chiral capillary electrophoresis: facts and fiction on the reproducibility of resolution with randomly substituted cyclodextrins

Comparative enantioseparation of the enantiomers of 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate was performed with cyclodextrin (CD)-modified capillary electrophoresis (CE). Two single isomers, beta-CD, heptakis(2,3,6-tri-O-methyl)-beta-CD (TM-beta-CD), and heptakis(2,6-di-O-methyl)-beta-CD (DM-beta-CD) of 98% purity as well as heptakis(2,3-di-O-acetyl)-beta-CD were used and compared in terms of resolution power to randomly methylated and corresponding acetylated beta-CDs, which were synthesized in our laboratory. The methylated ones were characterized by means of matrix-assisted laser desorption/ionization-time of flight-(MALDI-TOF) mass spectrometry. By testing defined mixtures of single isomers and comparing their resolution power to randomly substituted CDs of similar degree of substitution we could show, that a simple characterization by the average molecular degree of substitution (DS) is not sufficient. In order to get reproducible results, a clearly defined substitution pattern is necessary, which is not given using randomly substituted CDs. Taken together, a validation of a chiral separation with "undefined" CD derivatives is almost impossible.     

Comparative study on the enantiomer separation of 1,1'-binaphthyl-2,2'diyl hydrogenphosphate and 1,1'-bi-2-naphthol by liquid chromatography and capillary electrophoresis using single and combined chiral selector systems

The chiral recognition ability of single and dual selectors, that were used as additives, have been investigated by HPLC and CE. Native beta- and gamma-cyclodextrins, permethylated beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, cholic acid and taurodeoxycholic acid sodium salts were applied as chiral selectors, whereas the atropisomers of 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate, and 1,1'-bi-2-naphthol served as model compounds. It was found that all investigated selectors, except for gamma-cyclodextrin, display the same affinity pattern for binaphthyl enantiomers, i.e., binding the S more strongly than the R enantiomer. However, the differences in the phase distribution of chiral selectors led to the opposit elution order of enantiomers: with cyclodextrins, the first eluted is S enantiomer, while R is the first eluted for bile salts. Under the conditions studied, cyclodextrins (except gamma-cyclodextrin), as well as cholic acid sodium salts acting singly, enable the separation of 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate enantiomers both by HPLC and CE methods, while 1,1'-bi-2-naphthol enantiomers were resolved only under CE conditions with permethylated cyclodextrin or bile salts. In both techniques the application of dual systems could improve resolution or make it worse (oreven cancel), depending on the sign of enantioselectivity of particular selectors, their concentrations and localization: mobile or stationary phase. It has been found that the mechanism of separation as well as interactions occurring between two selectors may be followed by using combined HPLC and CE methods. The obtained results proved that, as well as beta-CD, TM-beta-D and gamma-CD also form inclusion complexes with cholic acid sodium salts. The reversal of elution order may be realized by two procedures: changing a single selector, i.e., cyclodextrin on cholic acid sodium salt or vice versa, and by changing the proportion of selectors in the combined bile salt-cyclodextrin system.     

Proton NMR assignments for R,S-1,1'-binaphthol (BN) and R,S-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BNDHP) interacting with bile salt micelles

We report proton chemical shifts for two model chiral analytes that are commonly used in the study of micellar electrokinetic capillary chromatography (MEKC), R,S-1,1'-binaphthol (1, BN) and R,S-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2, BNDHP), in the absence and presence of monomers and micelles of sodium cholate and sodium deoxycholate. The analytes undergo fast exchange in and out of the micelles, which perturbs the analytes' chemical shifts, and which we use to resolve some resonances that are degenerate at both 300 and 600 MHz. Although BN and BNDHP are simple molecules, the proton assignments are only unambiguously established with the aid of the exchange with micelles, an attractive alternative to other methodologies such as the use of paramagnetic shift reagents which may also cause spectral distortions. We rely also upon 2D-NOE spectra of samples in the presence of micelles to perform these assignments. Recently published assignments, which were based upon 2D-COSY spectroscopy, appear to be in error and are corrected here. Finally, we note that these shifts are information-rich reporters on the nature of the interactions of these model analytes with the micelles.     

Optimised separation of endogenous urinary components using cyclodextrin-modified micellar electrokinetic capillary chromatography

In this study both native and chemically modified cyclodextrins (CDs) were investigated as buffer additives to improve the micellar electrokinetic capillary chromatography (MEKC) separation of endogenous bioanalytes in human urine. The following CDs were investigated: alpha, beta, gamma-CDs; hydroxypropyl-alpha-CD, hydroxypropyl-beta-CD, methylated beta-CD, sulphated beta-CD, sulphobutyl ether-beta-CD and hydroxypropyl-gamma-CD. The separations were compared to MEKC without additives. The best improvement in peak resolution and separation of urine components was observed with the sulphated beta-CD. A four-factor three-level full factorial design study was conducted on voltage, temperature, pH and sulphated beta-CD molarity. The optimum conditions were 25 mM sodium tetraborate, pH 9.5, 75 mM sodium dodecyl sulphate (SDS) and 6.25 mM sulphated beta-CD and were able to resolve 70 peaks from a urine pool in 12 min. These optimum conditions have been successfully applied to a number of clinical samples.     

1, 1'-Binaphthyl-2, 2'-diamine Dihydrochloride: an Efficient Ligand for the N-Arylation of Imidazole with Aryl/heteroaryl Halides Catalyzed by CuI

Employing 1,1'-binaphthyl-2,2'-diamine(BINAM) dihydrochloride as an efficient and commercially available ligand, relatively mild and highly efficient copper-catalyzed coupling reactions of imidazole with aryl and heteroaryl halides have been developed. Various N-arylimidazoles could be synthesized in moderate to excellent yields.     

Enantioseparation of dihydropyridine derivatives by means of neutral and negatively charged beta-cyclodextrin derivatives using capillary electrophoresis

Employing capillary electrophoresis, the racemates of 29 acidic, neutral and basic dihydropyridines (DHPs) were separated by means of neutral and negatively charged cyclodextrins (CDs). Whereas the enantiomers of the acidic DHPs could be resolved with neutral CDs, mostly alpha- and beta-CD, the enantiomers of the neutral DHPs were only baseline-separated using the sulfobutyl ether-substituted beta-CD. Working in reversed polarity mode (detector at the anode) improved the peak shape and the resolution of the enantiomers. The racemates of the DHP bearing a secondary or tertiary amine function in the side chain at position 3 could be separated by using either the neutral gamma-CD or negatively charged CDs. The poor peak shape found with anionic CDs could be improved by the addition of methanol. The combination of gamma-CD and sulfated beta-CD allowed the detection of the minor enantiomer of lercanidipine (24) at less than 1% w/w.     

Stereostructure and thermodynamic stability of atropisomers of ortho-substituted 2,2′-diaryl-1,1′-binaphthalenes

A series of ortho-substituted 2,2′-aryl-1,1′-binaphthalenes were prepared via Negishi arylation of 2,2′-diiodo-1,1′-binaphthalene in good to high yields (65–95%) as an equilibrium mixtures of up to three atropisomers (unlike,unlike, like,unlike, and like,like). Thermodynamic stability parameters of the atropisomers were evaluated from VT NMR spectra by regression analysis. The DFT parameters calculated using CAM-B3LYP functional comprising solvent permittivity were, apart from the toluene solution, which was expected to interact with the aromatic solute, in qualitative agreement with the experimental values. In the case of the ditolyl derivative, the population of the atropisomers was confirmed by CD spectroscopy via comparison with the population-weighted averaged spectrum computed using the M06 functional. X-ray structure analyses of particular atropisomers of the dianisyl, dianilinyl, and dinaphthyl derivatives are also presented and discussed.     

高效液相色谱法手性分离联萘二酚苯甲酸酯对映体

采用Chirex(S)-LEU(S)-NEA、ChiralcelOD-H和ChiralpakAD-H手性色谱柱直接拆分了2′-羟基-1,1′-联萘-2-苯甲酸酯(HBNB)、1,1′-联萘-2,2′-二苯甲酸酯(BNDB)和2′-甲氧基-1,1′-联萘-2-苯甲酸酯(MBNB)对映体。分别考察了流动相组成、柱温和化合物结构对手性分离的影响。结果表明:3对联萘二酚苯甲酸酯对映体在ChiralpakAD-H柱上的拆分效果最好。当采用正己烷/异丙醇(40/60,v/v)为流动相时,HBNB、BNDB和MBNB对映体的分离因子(α)和分离度(Rs)分别为1.76、1.74、1.40和6.47、7.81、4.75。对比联萘二酚(BN)的分离,从联萘分子中2-位取代基、对映体出峰顺序和热力学参数等方面探讨了相关手性分离机理。     

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.     

高效液相色谱法测定1,1’-联萘-2,2’-二酚的光学纯度

用高效液相色谱法测定了1,1’-联禁-2,2’-二酚的光学纯度。色谱柱:Si-5柱,流动相:石油醚／乙醇（93／7,V／V）。方法简便、快速、准确,准确度为98.6％～101.6％,相对平均偏差为1.01％。     

Enantiomer separation of miconazole by capillary electrophoresis with dual cyclodextrin systems.

A cyclodextrin-modified micellar capillary electrophoretic method (MECC) was developed using mixtures of beta, cyclodextrins (beta-CD) and mono-3-O-phenylcarbamoyl-beta-CD as chiral additives for the chiral separation of miconazole with the dual CDs systems. The enantiomers were resolved using a running buffer of 50 mmol/L borate pH 9.5 containing 15 mmol/L beta-CD and 15 mmol/L mono-3-O-phenylcarbamoyl-beta-CD containing 50 mmol/L sodium dodecyl sulfate and 1 mol/L urea. A study of the respective influence of the beta-CD and the mono-3-O-phenylcarbamoyl-beta-CD concentration was performed to determine the optimal conditions with respect to the resolution. Good repeatability of the method was obtained.     

Recent innovations in the use of charged cyclodextrins in capillary electrophoresis for chiral separations in pharmaceutical analysis

A review is presented on the use of charged cyclodextrins (CDs) as chiral selectors in capillary electrophoresis (CE) for the separation of analytes in pharmaceutical analysis. An overview is given of theoretical models that have been developed for a better prediction of the enantiomeric resolution and for a better understanding of the separation mechanism. Several types of charged CDs have been used in chiral capillary electrophoretic separation (anionic, cationic, and amphoteric CDs). Especially the anionic CDs seem to be valuable due to the fact that many pharmaceutically interesting compounds can easily be protonated (e.g., amine groups). For that reason several anionic CDs are now commercially available. Cationic and amphoteric CDs are less common in chiral analysis and only a few are commercially available. Attention is paid to the most common synthesis routes and the characterization of the CDs used in chiral capillary electrophoretic separations. The degree of substitution in the synthesized CDs may vary from one manufacturer to another or even from batch to batch, which may have a detrimental effect on the reproducibility and ruggedness of the separation system. In Sections 4, 5, and 6 the applications of anionic, cationic, and amphoteric CDs for the chiral separation in CE are described. Many interesting examples are shown and the influence of important parameters on the enantioselectivity is discussed.     

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.