Chiral Discrimination Ability Research Articles

Comparative HPLC Enantioseparation of Thirty‐Six Aromatic Compounds on Four Columns of the Lux® Series: Impact of Substituents, Shapes and Electronic Properties

With the aim to define a combined computational/chromatographic empirical approach useful for the high-performance liquid chromatography (HPLC) method development of new chiral compounds, 36 racemic aromatic compounds with different chemical structures were used as test probes on four polysaccharide-based chiral stationary phases (CSPs) of the Lux series, namely Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-4, and Lux Amylose-2, using classical n-hexane/2-propanol mixtures as mobile phase. Electrostatic potential surfaces (EPSs) determined using Density Functional Theory (DFT) calculations were used to derive size, shape, and electronic properties of each analyte. Then a comparative HPLC screening was carried out in order to evaluate the impact of substituents, shapes, and electronic properties of the analytes on the chromatographic behavior as the column changes. The four CSPs showed good complementary recognition ability. The elution sequence was determined in 30 cases out of 36. The success rate to afford baseline separations (R(s) ≥ 1.5) was estimated: 29 compounds out of 36 showed baseline enantioseparation on at least one of the four selected CSPs. The combined computational-chromatographic screening furnished useful collective structure-chromatographic behavior relationships and a map of the chiral discrimination abilities of the considered CSPs towards the analytes. On this basis, the chromatographic behavior of new analytes on a set of polysaccharide-based CSPs can be mapped through the qualitative correlation of chromatographic parameters (k, α, R(s)) to computed molecular properties of the analytes.

Chiral discrimination and interaction mechanism between enantiomers and serum albumins

The chiral discrimination studies of biological system are theoretically and practically significant for the development of chiral drugs and life science. Our work has embarked upon the interaction between serum albumin (SA) (including human SA and bovine SA), R,S-1-(4-methoxyphenyl)ethylamine, and R,S-1-(3-methoxyphenyl)ethylamine. The formation of intermediate transition state, binding sites, and chiral discrimination ability can be investigated by ultraviolet-visible spectra and fluorescence spectra. Moreover, both the changes of hydrophobic microenvironment and energy transfer can be detected by synchronous fluorescence spectra and fluorescence lifetime.

Chiral separations in reversed-phase liquid chromatography: Evaluation of several polysaccharide-based chiral stationary phases for a separation strategy update

By application of the reversed-phase generic screening conditions of a separation strategy defined in Matthijs et al. (2004) [18], the chiral discrimination abilities of six recently commercialized polysaccharide-based columns, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, Lux Cellulose-4, Lux Amylose-2 and Sepapak-5, and of three classic ones, Chiralpak AD-RH, Chiralcel OD-RH and Chiralcel OJ-RH, were evaluated using a set of 58 compounds. Two mobile phases, an acidic and a basic, were sequentially applied on the columns. Using both mobile phases, a column set of Chiralcel OD-RH (or Lux Cellulose-1), Lux Cellulose-3 and Lux Amylose-2 gave the maximal number of cumulative separations, i.e. 51/58 (or 50), of which 35 (or 32) had baseline resolutions. Therefore, this set of systems was selected to update the screening step of the existing separation strategy. The selected columns were subsequently used to evaluate the applicability of the initial optimization steps, part of the existing RPLC strategy, using 66 different optimization cases. The existing optimization steps increased both the number of separations and of baseline separations by eight and by 18, respectively, relative to the screening results. Introduction of some modifications to the existing steps added eight more separations and three more baseline separations. In addition, a new optimization step for late eluting compounds was proposed and implemented. Based on these results, an updated chiral separation strategy in RPLC was defined.

Chiroptical Study of Chiral Discrimination by Amino Acid Based Ionic Liquids

The chiral discrimination ability of amino acid based chiral ionic liquids is studied using chiroptical luminescence techniques. A racemic mixture of dissymmetric europium tris(2,6-pyridinedicarboxylate) complexes are dissolved in five chiral ionic liquids, including l- and d-alanine methyl ester bis(trifluoromethanesulfonimide), l-leucine methyl ester bis(trifluoromethanesulfonimide), l-proline methyl ester bis(trifluoromethanesulfonimide), and tetrabutylammonium l-alanate. Circularly polarized luminescence spectra are measured for the samples over the 283-323 K temperature range. Analysis of the spectroscopic results shows that the amino acid methyl ester chiral ionic liquids show discrimination with a preference (handedness) that corresponds to the stereoisomer (l- vs d-). Most of the chiral ionic liquids show enthalpically dominated discrimination, but l-leucine methyl ester bis(trifluoromethanesulfonimide) shows entropically dominated chiral discrimination.

Optimization of the LC enantioseparation of chiral pharmaceuticals using cellulose tris(4-chloro-3-methylphenylcarbamate) as chiral selector and polar non-aqueous mobile phases

The resolving power of a new commercial polysaccharide-based chiral stationary phase, Sepapak-4, with cellulose tris(4-chloro-3-methylphenylcarbamate) coated on silica microparticles as chiral selector, was evaluated toward the enantioseparation of ten basic drugs with widely different structures and hydrophobic properties, using ACN as the main component of the mobile phase. A multivariate approach (experimental design) was used to screen the factors (temperature, n-hexane content, acidic and basic additives) likely to influence enantioresolution. Then, the optimization was performed using a face-centered central composite design. Complete enantioseparation could be obtained for almost all tested chiral compounds, demonstrating the high chiral discrimination ability of this chiral stationary phase using polar organic mobile phases made up of ACN and containing an acidic additive (TFA or formic acid), 0.1% diethylamine and n-hexane. These results clearly illustrate the key role of the nature of the acidic additive in the mobile phase.

Separation of stereoisomers of sertraline and its related enantiomeric impurities on a dimethylated β-cyclodextrin stationary phase by HPLC

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed and validated for evaluating the chiral discrimination ability of CYCLOBOND I 2000 DM chiral stationary phase (CSP) towards sertraline and its related enantiomers. The effect of pH, buffer concentration as well as nature of organic modifier, flow rate and temperature on enantioselectivity was investigated. The developed reversed-phase chromatographic conditions were able to separate not only the enantiomers of sertraline but also its process related chiral impurities. The method was validated for determination of enantiomeric purity of sertraline HCl in drug substances and formulations.

Chiral Recognition of Mandelic Acid on Quartz Crystal Microbalance by Vapor Diffused Molecular Assembly Method

This study presents a new approach for the highly selective recognition of chiral L/D-mandelic acid (MA) using a quartz crystal microbalance (QCM) with L-phenylalanine (L-Phe) as the selector. The immobilization of L-Phe on the gold surface of the QCM sensor was performed using a four steps layer-by-layer assembling procedure. The modification of the gold surface of the QCM sensor after each modification step was verified by the cyclic voltammetry, contact angle, FTIR, and QCM detection. The chiral recognition ability of L- and D-MA on the chiral surface was checked by sensing using the vapor diffused molecular assembly (VDMA) method with the QCM. The chiral discrimination factor between L- and D-MA, aplha(L-MA/D-MA), was found to be about 9. The L-Phe-modified QCM gold sensor also showed good stability and reusability. The high chiral discrimination ability of the modified surface might be the result of the different hydrogen bonding force between L- or D-MA and L-Phe.

Magnetic chiral ionic liquids derived from amino acids

Novel room temperature magnetic chiral ionic liquids derived from amino acids were synthesized and their magnetic properties as well as chiral discrimination abilities were investigated.

Chiral Protonated Amino Acid Ester Discrimination by Acyclic Chiral Hosts Including D-Mannofuranose Moieties in Fast Atom Bombardment Mass Spectrometry Coupled with the Enantiomer Labeled Guest Method

Chiral discrimination by novel chiral hosts 3 and 4, which consist of an oxyethylene chain and 2,3:5,6-di-O-cyclohexylidene-β-D-mannofuranose moieties at both ends, was examined considering several protonated amino acid isopropyl ester guests using fast atom bombardment mass spectrometry (FABMS) with the enantiomer deuterium-labeled guest method. Host 3 showed chiral discrimination toward several guests but with slightly smaller chiral discrimination abilities than host 2a, which consists of a bis-(oxyethylene) chain and 1,2:3,4-di-O-isopropylidene-α-D-galactopyranoside moieties at both ends. Host 4 showed no enantioselectivity, possibly because chiral hosts do not show a pseudo-ring conformation having large open spaces in complexations with a chiral guest in regard to the steric effects of cyclohexylidene groups. In addition, to understand the chiral recognition mechanisms, the binding sites of hosts 3 and 4 were elucidated by ultraviolet-visible (UV-VIS) and proton nuclear magnetic resonance (1H-NMR) spectroscopy.

Direct screening of chiral discrimination abilities of chiral hosts using mass spectrometry

A simultaneous estimation of the chiral discrimination abilities of several chiral hosts was demonstrated on the basis of one mass spectrum. The chiral host mixture, including H(1), H(2), H(3) ..., and H(m) (m: number of hosts) was prepared by etherification of several chiral alcohols with bistosylate of diethylene glycol. An equimolar mixture of a deuterium-labeled (S)- and unlabeled (R)-enantiomer of an amino acid isopropyl ester hydrochloride (G(S-dn) (+)Cl(-) and G(R) (+)Cl(-), n: number of deuterium atoms) was added to the chiral host mixture, and the FAB mass spectrum was measured to evaluate the chiral discrimination ability of each host in the mixture without isolation. The chiral discrimination ability of each host toward the guest is represented by the relative peak intensity of the diastereomeric complex ion pair, I(H(m) + G(R)((+)/I(H(m) + G(S-dn))(+) (=I(R)/I(S-dn) value). Several new hosts showed good chiral discrimination toward the guest.

Chiral Discrimination of Tolterodine Tartrate by Modified Cyclodextrins

The chiral discrimination ability of two β‐cyclodextrin derivatives (hosts) having a flexible pyrrolidinylidenesulfamido‐appended moiety has been studied for the enantiomers of tolterodine tartrate (guest). Quenching of the fluorescence intensities of guests was observed in the presence of hosts. The S‐enantiomer of the tolterodine tartrate was better recognized by these hosts. Enantioselectivity factors (α) and association constants (Ks) of the host–guest complexes were calculated.

Chiral recognition of amino acids by use of a fluorescent resorcinarene.

The spectroscopic properties of a chiral boronic acid based resorcinarene macrocycle employed for chiral analysis were investigated. Specifically, the emission and excitation characteristics of tetraarylboronate resorcinarene macrocycle (TBRM) and its quantum yield were evaluated. The chiral selector TBRM was investigated as a chiral reagent for the enantiomeric discrimination of amino acids using steady-state fluorescence spectroscopy. Chiral recognition of amino acids in the presence of the macrocycle was based on diastereomeric complexes. Results demonstrated that TBRM had better chiral discrimination ability for lysine as compared to the other amino acids. Partial least squares regression modeling (PLS-1) of spectral data for macrocycle-lysine guest-host complexes was used to correlate the changes in the fluorescence emission for a set of calibration samples consisting of TBRM in the presence of varying enantiomeric compositions of lysine. In addition, validation studies were performed using an independently prepared set of samples with different enantiomeric compositions of lysine. The results of multivariate regression modeling indicated good prediction ability of lysine, which was confirmed by a root mean square percent relative error (RMS%RE) of 5.8%.

High-performance liquid chromatography separation of enantiomers of flavanone and 2′-hydroxychalcone under reversed-phase conditions

A reversed-phase high-performance liquid chromatography (HPLC) method was developed for evaluating the chiral discrimination ability of Chiralpak IA chiral stationary phase (CSP) towards flavanone. The effect of the nature and pH buffer as well as nature of alcohol modifier on enantioselectivity was investigated. Comparative study of enantioseparation in reversed-phase and polar organic conditions indicated a significative improvement in resolution when aqueous-based eluents were used. The developed reversed-phase chromatographic method was able to separate the enantiomers of flavanone from its isomeric form, the 2′-hydroxychalcone. The stereochemical stability of flavanone was studied by classical off-column HPLC kinetic procedures in aqueous and non-aqueous media. It was clearly demonstrated that the 2′-hydroxychalcone was involved as intermediate in the on-column and off-column enantiomerization process of flavanone.

Chiral cyclohexane based fluorescent chemosensors for enantiomeric discrimination of aspartate

Some new chiral cyclohexyl based fluorescent anion receptors have been synthesized and their absolute configuration has been determined by using circular dichroism (CD). Complexation experiments have been carried out with several dicarboxylates, and stoichiometries and complexation constants for the corresponding complexes have been determined. The chiral discrimination ability of these ligands for chiral dicarboxylates has been studied and the best results have been obtained with TMA aspartate.

多糖誘導体による光学異性体分離

多糖誘導体による光学異性体分離

Improved Optical Enrichment of SWNTs through Extraction with Chiral Nanotweezers of 2,6-Pyridylene-Bridged Diporphyrins

Chiral single-walled carbon nanotubes (SWNTs) have left- and right-handed helical structures (M and P, respectively, according to the IUPAC nomenclature). In this report, optically active SWNTs were obtained through preferential extraction of (M)- or (P)-SWNTs with 2,6-pyridylene-bridged chiral diporphyrins 1. In the circular dichroism (CD) spectra, the SWNTs extracted with 1 exhibit much larger intensity than those extracted with 1,3-phenylene-bridged chiral diporphyrins 2, indicating an improved chiral discrimination ability of 1. In particular, (6,5)-SWNTs display the most intensified CD signals among the SWNTs extracted with 1. In addition, the SWNT extraction ability of 1 has been shown to be considerably enhanced in comparison to 2. These improved discrimination and extraction abilities of 1 are attributed to the formation of its more stable SWNT complex. Computer-calculated energy minimized structures for 1:(6,5)-SWNT complexes show that (R)- and (S)-1 form complexes preferentially with (M)- and (P)-(6,5)-SWNTs, respectively. These calculations also predict that the 1:(6,5)-SWNT complex is approximately 1.6 kcal mol-1 more stable than the corresponding complex of 2, accounting for the improved abilities of 1 in the chiral discrimination and extraction.

Determination of enantiomeric compositions of analytes using novel fluorescent chiral molecular micelles and steady state fluorescence measurements.

Novel fluorescent chiral molecular micelles (FCMMs) were synthesized, characterized, and employed as chiral selectors for enantiomeric recognition of non-fluorescent chiral molecules using steady state fluorescence spectroscopy. The sensitivity of the fluorescence technique allowed for investigation of low concentrations of chiral selector (3.0 x 10(-5) M) and analyte (5.0 x 10(-6) M) to be used in these studies. The chiral interactions of glucose, tartaric acid, and serine in the presence of FCMMs poly(sodium N-undecanoyl-L-tryptophanate) [poly-L-SUW], poly(sodium N-undecanoyl-L-tyrosinate) [poly-L-SUY], and poly(sodium N-undecanoyl-L-phenylalininate) [poly-SUF] were based on diastereomeric complex formation. Poly-L-SUW had a significant fluorescence emission spectral difference as compared to poly-L-SUY and poly-L-SUF for the enantiomeric recognition of glucose, tartaric acid, and serine. Studies with the hydrophobic molecule alpha-pinene suggested that poly-L-SUY and poly-L-SUF had better chiral discrimination ability for hydrophobic analytes as compared to hydrophilic analytes. Partial-least-squares regression modeling (PLS-1) was used to correlate changes in the fluorescence emission spectra of poly-L-SUW due to varying enantiomeric compositions of glucose, tartaric acid, and serine for a set of calibration samples. Validation of the calibration regression models was determined by use of a set of independently prepared samples of the same concentration of chiral selector and analyte with varying enantiomeric composition. Prediction ability was evaluated by use of the root-mean-square percent relative error (RMS%RE) and was found to range from 2.04 to 4.06%.

Chiral Recognition of Zolmitriptan by Modified Cyclodextrins

AbstractThe two pyrrolidinylidenesulfamido‐modified β‐cyclodextrins (β‐CDs) 3 and 4 were prepared and studied for chiral discrimination of the enantiomers (R)‐ and (S)‐1 of zolmitriptan. The pyrrolidinylidenesulfamido spacer improved the chiral discrimination and binding abilities of these modified cyclodextrins. The hosts 3 and 4 showed higher selectivity for (S)‐1. The association constants (Table) and enantioselectivity factors were calculated for the complexes of (R)‐ and (S)‐1 with the β‐CDs 2–4. The formation of host⋅guest complexes was confirmed by 1H‐NMR studies.

Chiral Discrimination of D- and L-Amino Acids Using Iodinated Tyrosines as Chiral References: Effect of Iodine Substituent

L-Tyrosine and iodinated L-tyrosines, i.e., 3-iodo-L-tyrosine and 3,5-diiodo-L-tyrosine, are successfully used as chiral references for the chiral discrimination of aliphatic, acidic, and aromatic amino acids. Chiral discrimination is achieved by investigating the collision-induced dissociation spectra of the trimeric complex [Cu(II)(ref)(2)(A) - H](+) ion generated by electro spraying the mixture of D- or L-analyte amino acid (A), chiral reference ligand (ref) and M(II)Cl(2) (M = Ni and Cu). The relative abundances of fragment ions resulted by the competitive loss of reference and analyte amino acids are considered for measuring the degree of chiral discrimination by applying the kinetic method. The chiral discrimination ability increases as the number of iodine atom increases on the aromatic ring of the reference and the discrimination is better with Cu when compared with Ni. A large chiral discrimination is obtained for aliphatic and aromatic amino acids using iodinated L-tyrosine as the reference. Computational studies on the different stabilities of the diastereomeric complexes also support the observed differences measured by the kinetic method. The suitability of the method in the measurement of enantiomeric excess over the range of 2% to 100% ee with relative error 0.28% to 1.6% is also demonstrated.

Role of the weak interactions in enantiorecognition of racemic dihydropyrimidinones by novel brush‐type chiral stationary phases

The chiral discrimination ability of two recently prepared chiral stationary phases (CSP 1 and CSP 2), based on a leucine derived chiral selector, was tested for the enantiomers of dihydropyrimidone (DHPM) derivatives and compared with the commercially available Hyun-leucine CSP 3 and classical Pirkle-leucine CSP 4. By combining all of these CSPs, the enantiomers of all DHPM derivatives used in this study can be properly resolved. Particularly good enantioresolutions were achieved for thioureide derivatives, such as Monastrol. The results presented show that sulfur-aromatic interactions are meritorious for these very good separations.