Enantioselective anion exchangers based on cinchona alkaloid‐derived carbamates: Influence of C8/C9 stereochemistry on chiral recognition

Four diastereomeric chiral stationary phases (CSPs) based on quinine, quinidine, epiquinine, and epiquinidine tert‐butyl carbamate selectors were synthesized and evaluated under ion exchange HPLC conditions with a set of racemic N‐acylated and N‐oxycarbonylated α‐amino acids as selectands. The enantioseparation potential of quinine‐ and quinidine‐derived CSPs proved to be far superior to that of their C₉‐epimeric congeners. The absolute configuration of C₉ stereogenic center of the cinchonan backbone of these selectors was identified as the structural feature controlling the elution order. Guided by an X‐ray structure of a most favorable selector–selectand complex and the observed chromatographic enantioseparation data, a chiral recognition model was advanced. The contributions of ion‐pairing, π–π donor–acceptor, hydrogen bonding and steric interactions were established as crucial factors. Chirality 11:522–528, 1999. © 1999 Wiley‐Liss, Inc.     

Evaluation of "click" binaphthyl chiral stationary phases by liquid chromatography

Two "click" binaphthyl chiral stationary phases were synthesized and evaluated by liquid chromatography. Their structures incorporate S-(-)-1,1'-binaphthyl moiety as the chiral selector and 1,2,3-triazole ring as the spacer. These chiral stationary phases (CSPs) allowed the efficient resolution for a wide range of racemic BINOL derivatives, particularly for nonpolar diether derivatives and 3-phenyl indolin-2-one analogs. The chromatographic data showed that the π-π interaction was crucial for enantiorecognition of these CSPs. Loss of enantioselectivity observed on CSP3, which are lacking the triazole ring linkage, indicated that the triazole ring linkage took part in the enantioseparation process, although it was remote from the chiral selector of the CSP. The substitution of the phenyl group at 6 and 6' positions can significantly improve the separation ability of the CSP. The chiral recognition mechanism was also investigated by tracking the elution orders and studying the thermodynamic parameters.     

Combining the enantioselectivity of a cyclodextrin and a diamide selector in a mixed binary gas‐chromatographic chiral stationary phase

The present work reports on the investigation of a mixed binary chiral stationary phase (CSP) prepared by simultaneous attachment of permethylated‐β‐cyclodextrin ( D selector) and resorcinarene with pendant l ‐ or d ‐valine diamide groups ( L′ and D′ selectors, respectively) to a polysiloxane matrix via platinum‐catalyzed hydrosilylation. The gas‐chromatographic investigation of a number of racemates on the four different CSPs ( D, D′, DD′, and DL′ ) showed that the enantioselectivity of the individual chiral selectors was retained in the mixed binary CSPs. As a consequence, hydrocarbons, underivatized alcohols, ketones, and almost all proteinogenic amino acid derivatives could be separated simultaneously on each of the mixed CSPs. Matched and mismatched cases of enantioseparation on the mixed binary CSPs were observed but turned out to be of minor importance for enantiomeric separation. In general, more racemates were separated with α ≥ 1.02 on the mixed phases as compared to the single phases. In order to analyze the influence of the presence of the diamide selector on the enantioselectivity of the cyclodextrin selector, a mixed ternary CSP containing the selector D and a racemic mixture of the selectors D′ and L′ [ D ( D′L′ )] was prepared and investigated. Merits and limitations of the approach of mixed binary CSPs are discussed. © 2005 Wiley‐Liss, Inc. Chirality     

Immobilization of (1S,2R)-(+)-2-amino-1,2-diphenylethanol derivates on aminated silica gel with different linkages as chiral stationary phases and their enantioseparation evaluation by HPLC

A chiral selector was prepared through the reaction between (1S,2R)-(+)-2-amino-1,2-diphenylethanol and phenyl isocyanate. This selector was immobilized on aminated silica gel, respectively, with bifunctional group linkers of 1,4-phenylene diisocyanate, methylene-di-p-phenyl diisocyanate, and terephthaloyl chloride to produce corresponding three chiral stationary phases. The prepared compounds and chiral stationary phases were characterized by FT-IR, elemental analysis, (1)H NMR, and solid-state (1)H NMR. The enantioseparation ability of these chiral stationary phases was evaluated with structurally various chiral compounds. The chiral stationary phase prepared with 1,4-phenylene diisocyanate as linker showed excellent enantioseparation ability. The influence of different linkages on the enantioseparation was discussed.     

π-Facial hydrogen bonding in the chiral resolving agent 2,2,2-trifluoro-1-(9-anthryl)-ethanol and its racemic modification

2,2,2-Trifluoro-(9-anthryl)-ethanol (TFAE) has been extensively used, in its pure enantiomeric forms, as a chiral solvating agent in nuclear magnetic resonance spectroscopy (NMR). It has also played an important role in the development of chiral stationary phases in liquid chromatography (LC). X-ray crystallography of the enantiomeric and racemic crystals shows, in both cases, the formation of an intermolecular hydrogen bond between the O? H and the π-face of one of the rings of the anthracene aromatic system.¹ Few examples of such hydrogen bonding have been published previously, and those that have are not as clear cut as in this case. An explanation for the hydrogen bonding is sought using molecular modelling via the PM3 analytically derived molecular electrostatic potentials. Using NMR and dynamic lineshape analysis, the barrier to rotation about the aryl-carbon bond is estimated, indicating the C? CF₃ bond to be perpendicular to the anthracene axis in nonpolar solution. This conformation is identical to the conformation in the crystal. Evidence is also presented to support the formation of intermolecular π-facial hydrogen bonding in TFAE solutions. It is thought that such hydrogen bonding may be implicated in chiral recognition using this compound. © 1994 Wiley-Liss, Inc.     

Experimental and computational studies of enantioseparation of structurally similar chiral compounds on amylose tris(3,5‐dimethylphenylcarbamate)

The enantioseparation of 14 structurally similar chiral solutes, with one or two chiral centers, are studied for a commercially important polysaccharide‐based chiral stationary phase, amylose tris(3,5‐dimethylphenylcarbamate) (ADMPC). Among these solutes, only two solutes show significant enantioresolutions of 2 to 2.5 in n‐hexane/2‐propanol (90/10, v/v) at 298 K. The retention factors of the chiral solutes vary significantly from 0.7 to 7.0, and they are compared with those of simpler nonchiral solutes having similar but fewer functional groups. The sorbent–solute H‐bonding interactions between the solute functional groups and the polymer C?O and NH functional groups are probed with attenuated total reflection infrared spectroscopy (ATR‐IR). The H‐bonding interactions of the polymer C?O and NH groups with the solutes result in changes in the IR amide band wavenumbers of ADMPC upon solute adsorption. The nanostructure of an ADMPC cavity and the potential interactions with the chiral solutes are proposed based on the sorbent–solute–solvent HPLC data, the sorbent–solute IR data, and the sorbent–solute molecular dynamics (MD) simulations. The results are consistent with the three point attachment hypothesis and indicate that a significant enantioresolution in ADMPC requires at least three different interaction sites for simultaneous H‐bonds and phenyl–phenyl interactions for phenylpropylamine (PPA) and various structurally similar chiral solutes. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

GC Separation of Enantiomers of Alkyl Esters of 2‐Bromo Substituted Carboxylic Acids Enantiomers on 6‐TBDMS‐2,3‐di‐alkyl‐ β‐ and γ‐Cyclodextrin Stationary Phases

The gas chromatographic separation of enantiomers of 2‐Br carboxylic acid derivatives was studied on four different 6‐TBDMS‐2,3‐di‐O‐alkyl‐ β‐ and ‐γ‐CD stationary phases. The differences in thermodynamic data {ΔH and –ΔS} for the 15 structurally related racemates were evaluated. The influence of structure differences in the alkyl substituents covalently attached to the stereogenic carbon atom, as well as in the ester group of the homologous analytes, and the selectivity of modified β‐ and γ‐ cyclodextrin derivatives was studied in detail. The cyclodextrin cavity size, as well as elongation of alkyl substituents in positions 2 and 3 of 6‐TBDMS‐β‐CD, also affected their selectivity. The quality of enantiomeric separations is influenced mainly by alkyl chains of the ester group of the molecule and this appears to be independent of the CD stationary phase used. In some cases the separations occur as the result of external adsorption rather than inclusion complexations with the chiral selector. It was found that the temperature dependencies of the selectivity factor were nonlinear. Chirality 26:279–285, 2014. © 2014 Wiley Periodicals, Inc.     

Enantioseparation of flurbiprofen enantiomers using chiral ionic liquids by liquid‐liquid extraction

Flurbiprofen is a kind of nonsteroidal anti‐inflammatory drug, which has been widely used in clinic for treatment of rheumatoid arthritis and osteoarthritis. It has been reported that S‐flurbiprofen shows good performance on clinic anti‐inflammatory treatment, while R‐enantiomer almost has no pharmacological activities. It has important practical values to obtain optically pure S‐flurbiprofen. In this work, chiral ionic liquids, which have good structural designability and chiral recognize ability, were selected as the extraction selector by the assistance of quantum chemistry calculations. The distribution behaviors of flurbiprofen enantiomers were investigated in the extraction system, which was composed of organic solvent and aqueous phase containing chiral ionic liquid. The results show that maximum enantioselectivity up to 1.20 was attained at pH 2.0, 25°C using 1,2‐dichloroethane as organic solvent, 1‐butyl‐3‐methylimidazole L‐tryptophan ([Bmim][L‐trp]) as chiral selector. The racemic flurbiprofen initial concentration was 0.2 mmol L^?1, and [Bmim][L‐trp] concentration was 0.02 mol L^?1. Furthermore, the recycle of chiral ionic liquids has been achieved by reverse extraction process of the aqueous phase with chiral selector, which is significant for industrial application of chiral ionic liquids and scale‐up of the extraction process.     

Enantiomeric Separation of Bicyclo[2.2.2]octane‐Based 2‐Amino‐3‐Carboxylic Acids on Macrocyclic Glycopeptide Chiral Stationary Phases

Direct high‐performance liquid chromatographic (HPLC) separation of four bicyclo[2.2.2]octane based 2‐amino‐3‐carboxylic acid enantiomers were developed on chiral stationary phases (CSPs) containing different macrocyclic glycopeptide antibiotic selectors. The analyses were performed under reversed‐phase, polar organic and polar ionic mode on macrocyclic‐glycopeptide‐based Chirobiotic T, T2, TAG, and R columns. The effects of the mobile phase composition including the acid and base modifier, the structure of the analytes, and the temperature on the separations were investigated. Experiments were achieved at constant mobile phase compositions on different stationary phases in the temperature range 5–40°C. Thermodynamic parameters were calculated from plots of ln k or ln α versus 1/T. It was recognized that the enantioseparations in reversed‐phase and polar organic mode were enthalpically driven, but under polar‐ionic conditions entropically driven enantioseparation was observed as well. Baseline separation and determination of elution sequence were achieved in all cases. Chirality 26:200–208, 2014. © 2014 Wiley Periodicals, Inc.     

Evaluation of the macrocyclic antibiotic LY333328 as a chiral selector when used as a mobile phase additive in narrow bore HPLC

The macrocyclic antibiotic LY333328 has been evaluated as a chiral selector for the enantioseparation of nine dansylated amino acids. This macrocyclic glycopeptide was used as a chiral mobile phase additive (CMPA) in conjunction with narrow bore high‐performance liquid chromatography (HPLC). The key mobile phase parameters of LY333328 concentration and buffer pH were varied, along with variations in stationary phases consisting of C8, phenyl, cyano, and silica. After observing and plotting changes in retention and resolution based on corresponding variation in these parameters, a better understanding of the behavior of this chiral selector was obtained. The pK_a values of the dansyl amino acid analytes and LY333328 were measured and used to gain a better understanding of the microenvironment in which these enantioseparations occur. Optimized conditions resulted in the baseline separation of eight of nine dansyl amino acids. Chirality 11:75–81, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis of polymer-type chiral stationary phases and their enantioseparation evaluation by high-performance liquid chromatography

Two new chiral polymers of different molecular weights were synthesized by the copolymerization of (1R,2R)-(+)-1,2-diphenylethylenediamine, phenyl diisocyanate and terephthaloyl chloride. The polymers were immobilized on aminated silica gel to afford two chiral stationary phases. The polymers and the corresponding chiral stationary phases were characterized by Fourier transform-IR, elemental analysis, 1H and 13C NMR. The surface coverages of chiral structural units on the chiral stationary phases were estimated as 0.27 and 0.39 mmol/g, respectively. The enantioseparation ability of these chiral stationary phases was evaluated with a variety of chiral compounds by high-performance liquid chromatography. The effects of the organic additives, the composition of mobile phases, and the injection amount of sample on enantioseparation were investigated. A comparison of enantioseparation ability between these two chiral stationary phases was made. It was believed that the chain length of polymeric chiral selector significantly affected the enantioseparation ability of corresponding chiral stationary phase.     

New chiral stationary phases based on xanthone derivatives for liquid chromatography

Six chiral derivatives of xanthones (CDXs) were covalently bonded to silica, yielding the corresponding xanthonic chiral stationary phases (XCSPs). The new XCSPs were packed into stainless‐steel columns with 150 x 4.6 mm i.d. Moreover, the greening of the chromatographic analysis by reducing the internal diameter (150 x 2.1 mm i.d.) of the liquid chromatography (LC) columns was also investigated. The enantioselective capability of these phases was evaluated by LC using different chemical classes of chiral compounds, including several types of drugs. A library of CDXs was evaluated in order to explore the principle of reciprocity as well as the chiral self‐recognition phenomenon. The separation of enantiomeric mixtures of CDXs was investigated under multimodal elution conditions. The XCSPs provided high specificity for the enantiomeric mixtures of CDXs evaluated mainly under normal‐phase elution conditions. Furthermore, two XCSPs were prepared with both enantiomers of the same xanthonic selector in order to confirm the inversion order elution.     

Chiral recognition of binaphthyl derivatives: a chiral recognition model on the basis of chromatography, spectroscopy, and molecular mechanistic calculations for the enantioseparation of 1,1'-binaphthyl derivatives on cholic acid-bonded stationary phases.

In an effort to elucidate the mechanism of chiral discrimination of cholic acid-based stationary phases, the enantiomeric recognition ability of six chiral stationary phases (CSPs), prepared from differently substituted cholic acid derivatives, was evaluated in normal phase high-performance liquid chromatography (HPLC) with a series of 1,1'-binaphthyl compounds. The influence of structural variations of analytes on retention and enantioselectivity was investigated. Particularly high values of enantioselectivity were observed for the binaphthol enantiomers on a CSP prepared from the allyl 7 alpha,12 alpha-dihydroxy-3 alpha-phenylcarbamoyloxy-5 beta-cholan-24-oate. The complexes of this chiral selector with both enantiomers of binaphthol were studied as models for the interactions responsible for the enantioseparation with the cholic acid-based stationary phases. The 1:1 stoichiometry of the complex in solution was determined by UV titration. The chiral selector dissolved in chloroform exhibited a chiral discrimination for the binaphthol in (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopies. Some aromatic proton and carbon resonances of binaphthol were clearly separated into a pair of peaks due to enantiomers in the presence of the chiral selector. Moreover, on the basis of molecular mechanics calculation, a chiral discrimination model was proposed which nicely explains the relevant chromatographic behavior of the 1,1'-binaphthyl derivatives.     

Comparison of separation performances of amylose‐ and cellulose‐based stationary phases in the high‐performance liquid chromatographic enantioseparation of stereoisomers of β‐lactams

High‐performance liquid chromatographic methods were developed for the separation of the enantiomers of 19 β‐lactams. The direct separations were performed on chiral stationary phases containing either amylose‐tris‐3,5‐dimethylphenyl carbamate, (Kromasil® AmyCoat? column) or cellulose‐tris‐3,5‐dimethylphenyl carbamate, (Kromasil® CelluCoat? column) as chiral selector. The different methods were compared in systematic chromatographic examinations. The separations were carried out with good selectivity and resolution. The AmyCoat? and CelluCoat? columns appear to be highly complementary. The best separations of bi‐ and tricyclic β‐lactam stereoisomers were obtained with the AmyCoat? column, whereas the 4‐aryl‐substituted β‐lactams were better separated on the CelluCoat? column. The elution sequence was determined in all cases; no general rule could be established. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Liquid and subcritical fluid chromatographic enantioseparation of Nα‐Fmoc proteinogenic amino acids on Quinidine‐based zwitterionic and anion‐exchanger type chiral stationary phases. A comparative study

Stereoselective high‐performance liquid chromatographic and subcritical fluid chromatographic separations of 19 N^α‐Fmoc proteinogenic amino acid enantiomers were carried out by using Quinidine ‐based zwitterionic and anion‐exchanger‐type chiral stationary phases Chiralpak ZWIX(−) and QD‐AX. For optimization of retention and enantioselectivity, the ratio of bulk solvent components (MeOH/MeCN, H₂O/MeOH, or CO₂/MeOH) and the nature and concentration of the acid and base additives (counter‐ and co‐ions) were systematically varied. The effect of column temperature on the enantioseparation was investigated and thermodynamic parameters were calculated from the van't Hoff plots ln α vs. 1/T. The thermodynamic parameters revealed that the enantioseparations were enthalpy‐driven. The elution sequence was determined in all cases and with the exception of Fmoc‐Cys(Trt)‐OH, it was identical on both chiral stationary phases whereby the L‐enantiomers eluted before the D‐enantiomers.     

Synthesis of dendrimer‐type chiral stationary phases based on the selector of (1S,2R)‐(+)‐2‐Amino‐1,2‐diphenylethanol derivate and their enantioseparation evaluation by HPLC

In our recent work, a series of dendritic chiral stationary phases (CSPs) were synthesized, in which the chiral selector was L‐2‐(p‐toluenesulfonamido)‐3‐phenylpropionyl chloride (selector I), and the CSP derived from three‐generation dendrimer showed the best separation ability. To further investigate the influence of the structures of dendrimer and chiral selector on enantioseparation ability, in this work, another series CSPs ( CSPs 1‐4 ) were prepared by immobilizing (1S,2R)‐1,2‐diphenyl‐2‐(3‐phenylureido)ethyl 4‐isocyanatophenylcarbamate (selector II) on one‐ to four‐generation dendrimers that were prepared in previous work. CSPs 1 and 4 demonstrated the equivalent enantioseparation ability. CSPs 2 and 3 showed the best and poorest enantioseparation ability respectively. Basically, these two series of CSPs exhibited the equivalent enantioseparation ability although the chiral selectors were different. Considering the enantioseparation ability of the CSP derived from aminated silica gel and selector II is much better than that of the one derived from aminated silica gel and selector I, it is believed that the dendrimer conformation essentially impacts enantioseparation. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Preparation and chromatographic performance of a multifunctional immobilized chiral stationary phase based on dialdehyde microcrystalline cellulose derivatives

A novel high‐performance liquid chromatography (HPLC) multifunctional immobilized chiral stationary phase was prepared by bonding dialdehyde microcrystalline cellulose to aminosilica via Schiff base reaction and then derivatized with 3,5‐dimethylphenyl isocyanate. The HPLC multifunctional immobilized chiral stationary phase could not only achieve chiral separation but also achieve achiral separation. Chiral separation evaluation showed that 1‐(1‐naphthyl)ethanol and mandelonitrile got separation in normal phase (NP) mode. Ranolazine, benzoin ethyl ether, metalaxyl, and diclofop were successfully separated in reversed phase (RP) mode. Aromatic compounds such as polycyclic aromatic hydrocarbons (PAHs), anilines, and aromatic acids were selected as analytes to investigate the achiral separation performance of the multifunctional immobilized chiral stationary phase in NP and RP modes. The achiral separation evaluation showed that six PAHs could get good separation within 10 minutes in NP mode. Four aromatic acids were well separated in RP mode. The retention mechanism of aromatic compounds on the stationary phase was discussed, founding that π‐π interaction, π‐π electron‐donor‐acceptor (EDA) interaction, and hydrogen bonding interaction played important roles during the achiral separation process. This multifunctional immobilized chiral stationary phase had the advantages of simple bonding steps, short reaction time, and no need for space arm.     

Mechanism of chiral recognition in the enantioseparation of 2-aryloxypropionic acids on new brush-type chiral stationary phases

New brush-type chiral stationary phases (CSP I-IV) comprising N-3,5,6-trichloro-2,4-dicyanophenyl-L-alpha-amino acids (1-4) were prepared by binding of chiral selectors 1-4 to gamma-aminopropyl silica gel. To check the role of excess free aminopropyl groups, CSP V was prepared by binding N-3,5,6-trichloro-2,4-dicyanophenyl-L-alanyl-(3-triethoxysilyl)propylamide to unmodified silica gel. The best separation of racemic 2-aryloxypropionic acids (TR-1-13) was obtained with CSP I; the -(-)-S enantiomer were regularly eluted first, as determined by a CD detector. The mechanism of chiral recognition implies a synergistic interaction of carboxylic acid analyte with the chiral selector and achiral free gamma-aminopropyl units on silica. In fact, CSP V, which is lacking an achiral aminopropyl spacer, shows a lower separation ability for 2-aryloxypropionic acids, but a similar enantioselective discrimination of esters TR-19-20, in comparison with CSP I. CSP I-IV retain unaltered separation ability after a few months of continuous work using a large number of various mobile phases.     

Evaluation of the Edman degradation product of vancomycin bonded to core‐shell particles as a new HPLC chiral stationary phase

A modified macrocyclic glycopeptide‐based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide‐based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide‐based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core‐shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography‐mass spectrometry with EDP was performed in approximately 3 minutes. Other highlights include simultaneous liquid chromatography separations of rac‐amphetamine and rac‐methamphetamine with VancoShell, rac‐pseudoephedrine and rac‐ephedrine with NicoShell, and rac‐dichlorprop and rac‐haloxyfop with TeicoShell.     

Investigations of molecular recognition aspects related to the enantiomer separation of 2-methoxy-2-(1-naphthyl)propionic acid using quinine carbamate as chiral selector: An NMR and FT-IR spectroscopic as well as X-ray crystallographic study

The chiral recognition mechanism of a cinchona alkaloid-based chiral stationary phase (CSP) showing high enantiomer discrimination potential for 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) was investigated. Conformational and structural analyses of the 1:1 complexes of 9-O-(tert-butylcarbamoyl) quinine selector (SO) and MalphaNP acid (selectand, SA) were carried out employing NMR spectroscopy in solution, Fourier-transform infrared (FT-IR) spectroscopy, and solid-state X-ray diffraction analysis. Intramolecular NOEs of a soluble analogue of the CSP afforded the conformational states of the free and complexed form of the selector. The (1)H-NMR spectra revealed that the free form of the SO constitutes anti-open as well as anti-closed and/or syn-closed conformers. Upon complexation with the (S)-MalphaNP acid enantiomer to form the more stable diastereomeric associate, a conformational transition of the selector takes place, resulting in the synthesis of the anti-open conformer nearly exclusively. FT-IR spectra reveal that, besides the primary ion-pairing interaction, stereoselective hydrogen bonding stabilizes the more stable complex via the amide hydrogen of the SO. X-ray diffraction analysis of 9-O-(tert-butylcarbamoyl)quinine and (S)-MalphaNP acid complex further revealed the occurrence of a bidentate H-bond-mediated ionic interaction between SO and SA as well as the lack of pi-pi interaction in the 1:1 complex, and corroborated the conclusions derived from spectroscopic and chromatographic studies.