Evaluation and Comparison of a 3,5‐Dimethylphenyl Isocyanate Teicoplanin with Phenyl Isocyanate Teicoplanin Chiral Stationary Phase Using RP‐HPLC

HPLC enantiomeric separations of 8 α‐amino acids were achieved using two self‐made chiral stationary phases (CSP)–phenyl isocyanate teicoplanin (Phe‐TE) and 3,5‐dimethylphenyl isocyanate teicoplanin (DMP‐TE), using reversed phase mobile phases. The Phe‐TE or the DMP‐TE CSP was prepared from the TE using derivative agents, phenyl isocyanate or 3,5‐dimethylphenyl isocyanate, respectively. The chromatographic results were given as the retention, selectivity, resolution factor and the enantioselective free energy difference corresponding to the separation of the two enantiomers. The effect of pH, organic modifier type and amount were discussed, and the stereoselectivities for two TE‐based CSPs were compared. The chiral selectivity factor for six α‐amino acids on DMP‐TE is somewhat bigger than that on Phe‐TE CSP under reversed phase (RP) mode. Comparison of the enantiomeric separations using self‐made Phe‐TE and DMP‐TE was conducted to gain a better understanding of the chiral recognition mechanism of the macrocyclic glycopeptide CSP.     

Amino Acid Ionic Liquids as Chiral Ligands in Ligand‐Exchange Chiral Separations

Recently, amino acid ionic liquids (AAILs) have attracted much research interest. In this paper, we present the first application of AAILs in chiral separation based on the chiral ligand exchange principle. By using 1‐alkyl‐3‐methylimidazolium L ‐proline (L ‐Pro) as a chiral ligand coordinated with copper(II), four pairs of underivatized amino acid enantiomers—dl ‐phenylalanine (dl ‐Phe), dl ‐histidine (dl ‐His), dl ‐tryptophane (dl ‐Trp), and dl ‐tyrosine (dl ‐Tyr)—were successfully separated in two major chiral separation techniques, HPLC and capillary electrophoresis (CE), with higher enantioselectivity than conventionally used amino acid ligands (resolution (R_s)=3.26–10.81 for HPLC; R_s=1.34–4.27 for CE). Interestingly, increasing the alkyl chain length of the AAIL cation remarkably enhanced the enantioselectivity. It was inferred that the alkylmethylimidazolium cations and L ‐Pro form ion pairs on the surface of the stationary phase or on the inner surface of the capillary. The ternary copper complexes with L ‐Pro are consequently attached to the support surface, thus inducing an ion‐exchange type of retention for the dl ‐enantiomers. Therefore, the AAIL cation plays an essential role in the separation. This work demonstrates that AAILs are good alternatives to conventional amino acid ligands for ligand‐exchange‐based chiral separation. It also reveals the tremendous application potential of this new type of task‐specific ILs.     

An Electrochemiluminesence Chiral Sensor for Propranolol Enantiomers Based on Functionalized Graphite‐like Carbon Nitride Nanosheets

Graphite‐like carbon nitride nanosheets (g‐C₃N₄) have been attracted considerable attention for their applications in catalysis and electrochemiluminesence (ECL) sensor. In this paper, a facile solvothermal method was employed to prepare the functionalized nanocomposites with metal salts cadmium carbonate (CdCO₃) and g‐C₃N₄ hybrids (g‐C₃N₄‐CdCO₃). The prepared materials were characterized by scanning electron microscope (SEM), X‐ray energy dispersive spectroscopy (EDX) and Fourier transform infrared spectra (FTIR). The nanocomposites was used not only as a new type luminophore but also as a chiral selector in this simple and sensitive ECL chiral sensor system for the recognition and detection of propranolol (Pro) enantiomers via quenching effect. The obvious difference of ECL signal of S‐Pro and R‐Pro was obtained. Thus, the sensor had the ability to distinguish Pro enantiomers. The mechanism of recognition was discussed by the theoretical calculation of binding constant and the water contact angle experiments. The sensor for Pro enantiomers was developed at wide concentration range from 0.001 to 1 mmol?L^?1. The sensor with excellent sensitivity, stability and reproducibility provide a new strategy based on ECL for chiral recognition and the ECL chiral sensor.     

Binding modes identification through molecular dynamic simulations: A case study with carnosine enantiomers and the Teicoplanin A2‐2‐based chiral stationary phase

In the present study, an in silico methodology able to define the binding modes adopted by carnosine enantiomers in the setting of the chiral recognition process is described. The inter‐ and intramolecular forces involved in the enantioseparation process with the Teicoplanin A2‐2 chiral selector and carnosine as model compound are successfully identified. This approach fully rationalizes, at a molecular level, the (S) < (R) enantiomeric elution order obtained under reversed‐phase conditions. Consistent explanations were achieved by managing molecular dynamics results with advanced techniques of data analysis. As a result, the time‐dependent identification of all the interactions simultaneously occurring in the chiral selector‐enantiomeric analyte binding process was obtained. Accordingly, it was found that only (R)‐carnosine is able to engage a stabilizing charge–charge interaction through its ionized imidazole ring with the carboxylate counter‐part on the chiral selector. Instead, (S)‐carnosine establishes intramolecular contacts between its ionized functional groups, that limit its conformational freedom and impair the association with the chiral selector unit.     

Selective response of antigen‐antibody reactions on chiral surfaces modified with 1,2‐diphenylethylenediamine enantiomers

This work reported a comparative analysis of the amperometric responses of antigen‐antibody reactions on two stable chiral surfaces which were modified with 1,2‐diphenylethylenediamine enantiomers. Alpha‐fetoprotein antibody and antigen (anti‐AFP and AFP) were selected as model systems. First, (1R,2R)‐1,2‐diphenylethylenediamine or (1S,2S)‐1,2‐diphenylethylenediamine was modified on the gold surface of the electrode through amide linkage to construct chiral surfaces. Then, anti‐AFP was immobilized on the chiral electrode surface by electrostatic and hydrogen bonding interactions. The electrochemical characteristics of the modified electrodes were studied via cyclic voltammetry. The selective current responses of antigen‐antibody reactions on chiral electrode surfaces for different incubation time and varying AFP concentrations were monitored. The antigen‐antibody reactions were greatly influenced by the chirality of 1,2‐diphenylethylenediamine enantiomers, and the amperometric responses obtained from the (1S,2S)‐1,2‐diphenylethylenediamine modified electrode was obviously stronger than that from the (1R,2R)‐1,2‐diphenylethylenediamine modified electrode. Such work may not only offer valuable reference to the research of chiral drugs, but also help to comprehend the high selectivity of chiral molecular species in biosystems. Copyright © 2011 John Wiley & Sons, Ltd.     

A chiral LC‐MS/MS method for the enantioselective determination of R‐(+)‐ and S‐(–)‐pantoprazole in human plasma and its application to a pharmacokinetic study of S‐(–)‐pantoprazole sodium injection

Pantoprazole, a proton pump inhibitor, is clinically used for the treatment of peptic diseases. An enantioselective LC‐MS/MS method was developed and validated for the simultaneous determination of pantoprazole enantiomers in human plasma. Pantoprazole enantiomers and the internal standard were extracted from plasma using acetonitrile. Chiral separation was carried on a Chiralpak IE column using the mobile phase consisted of 10 mm ammonium acetate solution containing 0.1% acetic acid–acetonitrile (28 : 72, v /v). MS analysis was performed on an API 4000 mass spectrometer. Multiple reactions monitoring transitions of m /z 384.1→200.1 and 390.1→206.0 were used to quantify pantoprazole enantiomers and internal standard, respectively. For each enantiomer, no apparent matrix effect was found, the calibration curve was linear over 5.00–10,000 ng/mL, the intra‐ and inter‐day precisions were below 10.0%, and the accuracy was within the range of –5.6% to 0.6%. This method was applied to the stereoselective pharmacokinetic studies in human after intravenous administration of S ‐(–)‐pantoprazole sodium injections. No chiral inversion was observed during sample storage, preparation procedure and analysis. While R ‐(+)‐pantoprazole was detected in human plasma with a slightly high concentration, which implied that S ‐(–)‐pantoprazole may convert to R ‐(+)‐pantoprazole in some subjects.     

Chiral Recognition of Tryptophan Enantiomers Based on β‐Cyclodextrin‐platinum Nanoparticles/Graphene Nanohybrids Modified Electrode

The nanohybrids which based on β‐cyclodextrin, platinum nanoparticles and graphene (β‐CD‐PtNPs/GNs) were successfully synthesized and characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FT‐IR) and electrochemical impedance spectroscopy (EIS). Then they were used to construct a simple and reliable chiral sensing platform to interact with tryptophan (Trp) enantiomers. Differential pulse voltammetry (DPV) was used to investigate the stereo selectivity of β‐CD‐PtNPs/GNs to Trp enantiomers. After interaction, the obvious difference of peak currents of L‐Trp and D‐Trp was obtained, indicating this strategy could be employed to chiral recognition of Trp enantiomers. Under the optimum conditions, the chiral sensor exhibited a good linear response to Trp enantiomers in a linear range of 5.0×10^?5 to 5.0×10^?3 M with a low limit of detection of 1.7×10^?5 M (S/N=3). This approach provided a new available platform to recognize and determine Trp enantiomers.     

(R)‐N,N,N‐Trimethyl‐2‐Aminobutanol‐Bis(Trifluoromethane‐Sulfon)Imidate Chiral Ionic Liquid Used as Chiral Selector in HPCE,HPLC, and CGC

Abstract

In this work, the (R)‐N,N,N‐trimethyl‐2‐aminobutanol‐bis(trifluoromethanesulfon)imidate chiral ionic liquid was first used in chromatography and exhibited a excellent chiral recognition ability in high performance capillary electrophoresis (HPCE), high performance liquid chromatography (HPLC), and capillary gas chromatography (CGC), which also showed for the first time that chrial ionic liquid was an effective chiral selector in HPCE and HPLC. The compounds that have been separated using this chiral ionic liquid at least included alcohol, amine, acid, and amino acid, et al. enantiomers. As the chiral ionic liquid can be easily synthesized from relatively inexpensive materials, it should have a great potentiality for chiral separation in chromatographic science.     

Synthesis of Chiral 2,5—Bis（oxazolinyl） thiophenes and Their Application as Chiral Shift Reagents for 1,1′—Bi—2—naphthol

A series of C2-symmetrical chiral 2,5-bis (4′-alkyloxazolin-2-yl) thiophenes (thiobox) have been synthesized from thiophene-2,5-dicarboxylic acid by sequential amidation with a chiral ethanolamine,conversion of hydroxyl to chloro group, and base-promoted oxazoline ring formation.As demonstrated by (-)-2,5-bis[4′-(S)-isopropyloxazolin-2′-yl] thiophene,these thiobox systems exhibited remarkable chirality recognition of 1,1′-bi-2-naphthol giving rise to pronounced shifts in the ^1H NMR signals of the latter axial chiral compound at the positions of C-3,C-4,C-5,and C-8.     

Facile enantioseparation and recognition of mandelic acid and its derivatives in self‐assembly interaction with chiral ionic liquids

Mandelic acid and its derivatives are important medical intermediates in the pharmaceutical industry. Different stereoisomers exhibited distinct biological properties to human bodies. Given that, enantioselective recognition and separation of mandelic acid are of great importance. In this study, four novel different types of chiral ionic liquids bearing designed functional groups were synthesized and successful enantioselective precipitation with mandelic acid and its derivatives. That is, (R, R)‐chiral ionic liquid 1 can coprecipitated with S‐mandelic acid and its derivatives was observed. In addition, good correlation coefficient is achieved by using electrospray mass spectrum at negative ion pattern for quick analysis of the enantioselective precipitation, which could be served as a method of enantioselective recognition. The possible intermolecular interactions are established after systematical studies by NMR spectroscopy and DFT calculations.     

Binding Behaviors for Different Types of DNA G‐Quadruplexes: Enantiomers of [Ru(bpy)2(L)]2+ (L=dppz,dppz‐idzo)

Polymorphic DNA G‐quadruplex recognition has attracted great interest in recent years. The strong binding affinity and potential enantioselectivity of chiral [Ru(bpy)₂(L)]²⁺ (L=dipyrido[3,2‐a:2′,3′‐c]phenazine, dppz‐10,11‐imidazolone; bpy=2,2′‐bipyridine) prompted this investigation as to whether the two enantiomers, Δ and Λ, can show different effects on diverse structures with a range of parallel, antiparallel and mixed parallel/antiparallel G‐quadruplexes. These studies provide a striking example of chiral‐selective recognition of DNA G‐quadruplexes. As for antiparallel (tel‐Na⁺) basket G‐quadruplex, the Λ enantiomers bind stronger than the Δ enantiomers. Moreover, the behavior reported here for both enantiomers stands in sharp contrast to B‐DNA binding. The chiral selectivity toward mixed parallel/antiparallel (tel‐K⁺) G‐quadruplex of both compounds is weak. Different loop arrangements can change chiral complex selectivity for both antiparallel and mixed parallel/antiparallel G‐quadruplex. Whereas both Δ and Λ isomers bind to parallel G‐quadruplexes with comparable affinity, no appreciable stereoselective G‐quadruplex binding of the isomers was observed. In addition, different binding stoichiometries and binding modes for Δ and Λ enantiomers were confirmed. The results presented here indicate that chiral selective G‐quadruplex binding is not only related to G‐quadruplex topology, but also to the sequence and the loop constitution.     

Nickel(II)‐assisted enantiomeric differentiation and quantitation of tadalafil by direct electrospray ionization mass spectrometry

A facile method based on electrospray mass spectrometry was established and validated for the differentiation of enantiomeric tadalafil isomers without using chiral chromatographic separation. The enantiomers were coupled with a chiral selector to form diastereomeric complex ions. Nickel–tadalafil complexes, [Ni^II(tadalafil)(l ‐Trp)‐H]⁺, produced a characteristic fragment ion at m /z 524 by loss of 1‐methyl‐1,6‐dihydropyrazine‐2,5‐dione via collision‐induced dissociation. The relative abundance of this fragment ion to the precursor contributed to differentiate tadalafil enantiomers, and energy‐resolved product‐ion spectra were applied to determine the molar composition of tadalafil in the mixture (R ,R and S ,S ) as well. In addition, the other two forms of stereomeric isomers of tadalafil (R ,S and S ,R ) could be also distinguished and analyzed by this method. The method was validated in different types of mass spectrometers (AB quadrupole time‐of‐flight and Bruker ion trap) and also verified by a chiral high‐performance liquid chromatography coupled with quadrupole time‐of‐flight. The chiral determination of tadalafil using MS method proved to be rapid (1‐min run time for each sample) and to have the same accuracy and precision comparable to chiral liquid chromatography mass spectrometry methods. This method provides an alternative to commonly used chromatographic technique for chiral determination and is particularly useful in rapid screening in enantioselective synthesis and enantiomeric impurity detection in pharmaceutical industry. Copyright © 2017 John Wiley & Sons, Ltd.     

Degradation and residues of indoxacarb enantiomers in rice plants,rice hulls and brown rice using enriched S‐indoxacarb formulation and enantiopure formulation

A chiral liquid chromatography–tandem high resolution mass spectroscopic method was developed for the analysis of indoxacarb enantiomers in rice plants, rice hulls and brown rice. Chiral separation of two enantiomers was carried out on a Superchiral S‐OD column maintained at 20°C and eluted with 0.3 mL/min methanol. Samples were extracted by acetonitrile solution with ultrasound and cleansed by dispersive solid‐phase extraction of 50 mg of primary secondary amine and 50 mg of C₁₈. This method was successfully used to study the degradation and residues of two enantiomers with enriched S‐indoxacarb (2.33S/1R) and pure S‐indoxacarb in rice plants. The half‐lives of R‐indoxacarb and S‐indoxacarb were 4.20–4.33 and 3.45–3.57 days in rice plants during the degradation of enriched S‐indoxacarb in Guizhou and Hunan, respectively, whereas the half‐lives of pure S‐indoxacarb were 2.68 and 3.69 days in Guizhou and Hunan, respectively. The results indicated that preferential S‐indoxacarb degradation occurred and that enantiomeric transformation was absent in the total experiment periods of pure S‐indoxacarb in rice plants. The final residue concentrations of indoxacarb enantiomers in brown rice were significantly less than those in rice plants and rice hulls in the same rice field after applying indoxacarb SC and indoxacarb EC.     

Enantioseparation of mandelic acid enantiomers in ionic liquid aqueous two-phase extraction systems

In the past decade, ionic liquids have received great attention owing to their potential as green solvent alternatives to conventional organic solvents. In this work, hydrophobic achiral ionic liquids (1-butyl-3-methylimidazolium-hexafluorophosphate([bmim][PF₆]), 1-octyl-3-methylimidazolium tetrafluoroborate([omim][BF₄])) were used as solvents in chiral liquid-liquid extraction separation of mandelic acid (MA) enantiomers with β-cyclodextrin (β-CD) derivatives as hydrophilic chiral selectors preferentially forming complexes with (R)-enantiomers. Factors affecting the separation efficiency were optimised, namely the type of the extraction solvents and β-CD derivatives, concentrations of the β-CD derivatives and MA enantiomers, pH, and temperature. Excellent enantioseparation of MA enantiomers was achieved in the ionic liquid aqueous two-phase extraction systems under the optimal conditions of pH 2.5 and temperature of 5°C with the maximum enantioselectivity (α) of 1.74. The experimental results demonstrated that the ionic liquid aqueous two-phase extraction systems with a β-CD derivative as the chiral selector have a strong chiral recognition ability, which might extend the application of ionic liquids in chiral separation.     

The Chemo‐selective Reaction of 2‐Amino‐N′‐arylbenzohydrazide and Ketonic Acid Catalyzed by Iodine for the Synthesis of Quinazoline Derivatives

The chemo‐selective reaction of 2‐amino‐N′‐arylbenzohydrazide and ketonic acid catalyzed by iodine was used to synthesize various 2,3‐dihydroquinazolin‐4(1H)‐ones efficiently. The use of levulinic acid furnished a series of 2,3,3a,4‐tetrahydropyrrolo[1,2‐a]quinazoline‐1,5‐diones in high yields, while acetobutyric acid only afforded the quinazoline skeletons without forming the second pyridine ring. Using alcohol as the solvent instead of ionic liquids, a subsequent esterification was performed with the carboxylic group of acetobutyric acid substrate in one‐pot manner.     

Synthesis,Structural Characterisation and Stereochemical Investigation of Chiral Sulfur‐Functionalised N‐Heterocyclic Carbene Complexes of Palladium and Platinum

Palladium and platinum complexes containing a sulfur‐functionalised N‐heterocyclic carbene (S‐NHC) chelate ligand have been synthesised. The absolute conformations of these novel organometallic S‐NHC chelates were determined by X‐ray structural analyses and solution‐phase 2D ¹H–¹H ROESY NMR spectroscopy. The structural studies revealed that the phenyl substituents on the stereogenic carbon atoms invariably take up the axial positions on the Pd‐C‐S coordination plane to afford a skewed five‐membered ring structure. All of the chiral complexes are structurally rigid and stereochemically locked in a chiral ring conformation that is either (R_s,S,R)‐λ or (S_s,R,R)‐δ in both the solid state and solution.     

基于杯[4]芳烃的对N-乙酰基-天冬氨酸盐对映选择性识别的荧光传感器

合成了携带有丹磺酰基荧光团和（1R,2R）- 或（1S,2S）-1,2-二苯基乙二胺键合单元的双臂杯[4]芳烃手性阴离子受体（1和2）。通过荧光光谱检测了受体对手性氨基酸阴离子的键和能力。非线型曲线拟合的结果表明受体（1或2）与N-乙酰基-L或D－天冬氨酸盐通过多重氢键的相互作用形成了1：1的络合物。并且展现了对N-乙酰基天冬氨酸盐对映体良好的对映选择性的荧光识别（受体1： K_ass(D)/ K_ass(L)=6.74;受体2： K_ass(L)/ K_{ass (D)}=6.48）。明显不同的荧光响应说明受体1和2能被用作为对N-乙酰基天冬氨酸盐的荧光化学传感器。     

Chiral NMR discrimination of the diastereoisomeric salts of the H3‐antagonist 2‐[3‐(1H‐imidazol‐4‐ylmethyl)piperidin‐1‐yl]‐1H‐benzimidazole

Diastereomeric salts with optically pure (S)‐α‐methoxy‐α‐(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H₃‐antagonist 2‐[3‐(1H‐imidazol‐4‐ylmethyl)piperidin‐1‐yl]‐1H‐benzimidazole. Chemical‐shift differences (Δδ) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2‐position of the imidazole ring. Copyright © 2009 John Wiley & Sons, Ltd.     

Comparison of Separation Efficiency of Macrocyclic Glycopeptide-Based Chiral Stationary Phases for the LC Enantioseparation of β-Amino Acids

Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation of enantiomers of eighteen unnatural β-amino acids, including several β-3-homo-amino acids. The direct separations of the underivatized analytes were performed on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG), vancomycin (Chirobiotic V and V2), and ristocetin A (Chirobiotic R) as chiral selectors. The effects of the organic modifier, mobile phase composition and pH on the separations were investigated. A comparison of the separation performances of the macrocyclic glycopeptide stationary phases revealed that the Chirobiotic T2 column exhibited better selectivity than the Chirobiotic T column for the separation of β-3-homo-amino acid enantiomers; vancomycin or ristocetin A exhibited lower selectivity. The elution sequence was determined in some cases: the S enantiomers eluted before the R enantiomers, with the exception of the Chirobiotic R column, where the elution sequence R < S was observed.     

X‐ray Photoelectron Spectroscopy of Pyridinium‐Based Ionic Liquids: Comparison to Imidazolium‐ and Pyrrolidinium‐Based Analogues

We investigate eight 1‐alkylpyridinium‐based ionic liquids of the form [C_nPy][A] by using X‐ray photoelectron spectroscopy (XPS). The electronic environment of each element of the ionic liquids is analyzed. In particular, a reliable fitting model is developed for the C 1s region that applies to each of the ionic liquids. This model allows the accurate charge correction of binding energies and the determination of reliable and reproducible binding energies for each ionic liquid. Shake‐up/off phenomena are determinedfor both C 1s and N 1s spectra. The electronic interaction between cations and anions is investigated for both simple ionic liquids and an example of an ionic‐liquid mixture; the effect of the anion on the electronic environment of the cation is also explored. Throughout the study, a detailed comparison is made between [C₈Py][A] and analogues including 1‐octyl‐1‐methylpyrrolidinium‐ ([C₈C₁Pyrr][A]), and 1‐octyl‐3‐methylimidazolium‐ ([C₈C₁Im][A]) based samples, where X is common to all ionic liquids.