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The article reports simple, rapid, and novel enantioselective reversed‐phase high‐performance liquid chromatography (RP‐HPLC) for separation of (−)‐(3R, 4R)‐ormeloxifene hydrochloride (d‐ORM) and (+)‐(3S, 4S)‐ormeloxifene hydrochloride (l‐ORM) (ORM, centchroman) using chiral stationary phase (Chiral‐AGP, Chiracel OJ‐RH, and ChiraDEX HR). The best enantiomeric separation was obtained on the ChiraDEX HR (α = 0.89, Rs = 1.9) column with a gradient mode elution using a combination of ammonium acetate (10 mM, pH 4.0) and methanol as a mobile phase. The flow rate and column oven temperature were 0.7 mL/min and 30°C, respectively. The detection limits (λmax 280 nm) for d‐ORM and l‐ORM were 0.170 and 0.169 µg/mL, whereas quantification limits were 0.516 and 0.512 µg/mL. The method was validated according to the International Council on Harmonization (ICH) regulatory Guidelines Q2 (R1) in terms of its accuracy, precision, sensitivity, linearity, specificity, robustness, and solution stability. The designed analytical method could be extended as a quality control tool for pharmaceutical quality assessments as well as isomeric quantification of ORM in industrial bulk manufacturing. [ABSTRACT FROM AUTHOR]

While β‐peptides have been paid attention due to their diverse secondary structures, their application to the design of low‐molecular‐weight gelators (LMWGs) is less explored. In this work, chiral cyclic β‐amino acid‐based β‐peptides were developed as ambidextrous LMWGs, wherein multiple hydrogen bonds between the amide moieties led to high gelation ability. Their molecular assembly was elucidated using spectroscopies, microscopy, and X‐ray analysis. Further, the supramolecular gel was used as a platform for the enantioselective extraction of (S)‐naproxen from its racemate under optimized conditions. These findings have expanded the utility of β‐peptides and shown the potential of supramolecular gels as a distinct dynamic medium for enantiomer separation. [ABSTRACT FROM AUTHOR]

The chirality of amino acids in extraterrestrial materials may provide an insight into the origin of the essential l-enantiopure amino acids in the terrestrial biosphere. In 2020, the Hayabusa2 mission succeeded in bringing back surface materials from the C-type asteroid (162173) Ryugu to the Earth. Amino acids were one of the targeted organic molecules to be studied in the Ryugu samples. To analyze the various structural isomers of amino acids, which were expected to be present, from the limited amount of the returned samples, the development of a highly-sensitive and selective analytical method was necessary. In the present study, a three-dimensional high-performance liquid chromatography (3D-HPLC) system has been developed for the enantioselective determination of five proteinogenic and three non-proteinogenic amino acids in the Ryugu samples, in which amino acids in the sample were separated by reversed-phase, anion-exchange and enantioselective columns after the fluorescence derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiozole. The applicability of the analytical system to the extraterrestrial samples was evaluated by analyzing several types of carbonaceous meteorites before applying the system to the Ryugu samples. In the analysis of the Ryugu samples, all of the target amino acids were successfully determined quantitatively. Non-proteinogenic amino acids including 2-amino-n-butyric acid, isovaline and norvaline, rarely present in the terrestrial environment, were found as almost racemic mixtures with 47.1 to 55.2%l.

Considering the greater pharmaceutical and clinical interest of triiodothyronine (T3) thyroid hormone, an effective D/L‐T3 enantiomer separation was performed on a crown ether‐based chiral stationary phase by LC–MS/MS. In optimal analytical condition and selected reaction monitoring mode, the two enantiomers of T3 were baseline separated within 10 min. The limit of detection and limit of quantitation were found to be 0.05 and 0.10 ng/μl; 0.20 and 0.50 ng/μl for D‐ and L‐T3, respectively. During validation, this method proved to be feasible, accurate as well as enantioselective and sensitive for the resolution of T3 enantiomers. For commercial D‐ and L‐T3 chemicals, the enantiomeric impurities as the other enantiomer were 0.11% and 4.61%. On the other hand, the impurity as D‐T3 for commercial pharmaceutical products (liothyronine sodium tablets, two suppliers) was 0.68% and 6.57%. [ABSTRACT FROM AUTHOR]

Chirality is a critical issue in pharmaceutics, forensic chemistry, therapeutic drug monitoring, doping control, toxicology, or environmental investigations as enantiomers of a chiral compound can exhibit different activities, i.e., one enantiomer can have the desired effect while the other one can be inactive or even toxic. To monitor enantioselective metabolism or toxicokinetic/toxicodynamic mechanisms in extremely low content in biological or environmental matrices, sample preparation is vital. The present review describes current status of development of liquid-phase microextraction approaches such as hollow fiber liquid-phase microextraction (HF-LPME), electromembrane extraction (EME), dispersive liquid-liquid microextraction (DLLME), and supramolecular solvent-based microextraction (SSME), used for sample preparation of enantiomers/chiral compounds. The advantages and limitations of the above techniques are discussed. Attention is also focused on chiral separation approaches commonly applied to study the stereo-selective metabolism or toxicokinetic/toxicodynamic mechanisms of enantiomers in the biological and environmental samples. [ABSTRACT FROM AUTHOR]

Inspired by biological helices (e.g., DNA), artificial helical polymers have attracted intense attention. However, precise synthesis of one‐handed helices from achiral materials remains a formidable challenge. Herein, a series of achiral poly(biphenyl allene)s with controlled molar mass and low dispersity were prepared and induced into one‐handed helices using chiral amines and alcohols. The induced one‐handed helix was simultaneously memorized, even after the chiral inducer was removed. The switchable induction processes were visible to naked eye; the achiral polymers exhibited blue emission (irradiated at 365 nm), whereas the induced one‐handed helices exhibited cyan emission with clear circularly polarized luminescence. The induced helices formed stable gels in various solvents with helicity discrimination ability: the same‐handed helix gels were self‐healing, whereas the gels of opposite‐handed helicity were self‐sorted. Moreover, the induced helices could separate enantiomers via enantioselective crystallization with high efficiency and switchable enantioselectivity. [ABSTRACT FROM AUTHOR]

Sorting single-chirality enantiomers is the ultimate goal for single-wall carbon nanotube (SWCNT) separation. In this work, aqueous two-phase extraction (ATPE) is used to obtain highly purified (>80%) left- and right-handed (6,5) SWCNTs with limited experimental steps. The optimized surfactant conditions are presented, and analytical ultracentrifugation (AUC) and near-infrared photoluminescence (PL) measurements are used to examine the surfactant wrapping and partition coefficient change conditions (PCCCs) required for separation. Our study provides valuable insights into the underlying mechanisms behind surfactant-assisted SWCNT separations and facilitates the use of SWCNT enantiomers in fundamental studies and applications in the future. [Display omitted] • Single-wall carbon nanotube enantiomers are prepared using a simple aqueous two-phase extraction method. • Different co-surfactant systems are examined to optimize the separation results. • Surfactant wrapping on both right- and left-handed (6,5) SWCNTs are investigated by analytical ultracentrifugation. • The partition coefficient change conditions are measured for handedness sorting. [ABSTRACT FROM AUTHOR]

There have been several reports of the enantiospecific adsorption of chiral compounds from solution onto ferromagnetic surfaces in applied magnetic fields. This work studies the kinetics of D‐ and L‐aspartic acid (Asp) adsorption onto a Ni(100) surface in a 0.45 T applied magnetic field under ultra‐high vacuum (UHV) conditions. Desorption studies performed after exposing the Ni(100) sample to L‐Asp revealed no influence of the applied magnetic field on the adsorption kinetics. Similarly, concurrent exposure of the Ni(100) surface to a mixture of isotopically labeled L*‐Asp and D‐Asp resulted in no detectable field induced differences in the relative enantiomer coverages adsorbed onto the surface. In summary, the presence of an applied magnetic field had no detectable influence on the adsorption kinetics of Asp enantiomers on a Ni(100) surface under UHV conditions. This is in contrast to the magnetic field induced adsorption enantiospecificity observed in solution phase. The possible origins of this discrepancy are considered. [ABSTRACT FROM AUTHOR]

The series of C2-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6′-diiodo-2,2′,4,4′-tetramethylbiphenyl-3,3′-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity. [ABSTRACT FROM AUTHOR]

Lipases are crucial in achieving stereoselective enantiomer separation for pure enantiomer production, as seen in pharmaceutical and chemical industries. Although empirical models like the Kazlauskas rule guide enantioselectivity, however, this rule is considered "soft knowledge" and lacks mechanistic depth. Advanced computational methods or "hard knowledge" approaches could yield more reliable enantioselectivity predictions, enhancing applications in stereoselective synthesis across various fields. A new covalent docking model has been developed that accounts for the stereochemistry of both intermediate compounds and the transition state at the catalytic site of Amano lipase. This model assesses enantioselectivity in resolving secondary alcohols, based on data from the Enamine Screening Collection. Analysis revealed two key stereocenters: one in the acetylated alcohol group and another formed when the ligand binds to Ser87 in the transition state complex. Only a specific S-configuration of these stereocenters results in the catalytic reaction product. Molecular dynamics showed that enantiomer discrimination in aromatic ligands relies on contacts with four key amino acids within the catalytic site. Specifically, hydrogen bonds between the NH atoms of His286, the alcohol oxygen (Oalc), and the Oγ of Ser87, as well as between the ligand's OH group and the NH atoms of Leu17 and Gln88, play a crucial role in facilitating successful substrate acetylation. These interactions create a favorable environment for the catalytic p rocess to proceed efficiently. [ABSTRACT FROM AUTHOR]

The 2‐Aryl‐2‐fluoroacetonitriles have garnered increasing interest as versatile building blocks in asymmetric synthesis. However, the configurational stability of these organofluorines is poorly understood and analytical methods that can be used to differentiate between their enantiomers remain underdeveloped. In this study, baseline high performance liquid chromatography (HPLC) enantioseparation of ten 2‐aryl‐2‐fluoroacetonitriles was achieved by screening frequently used chiral stationary phases. While Chiralcel OD, Chiralpak AD, and Chiralpak AS proved to be most broadly useful, preparative separation of the enantiomers of 2‐(2‐naphthyl)‐2‐fluoroacetonitrile was possible on Chiralcel OJ. This enabled racemization studies at various temperatures and in the presence of organic bases which showed that this compound is configurationally stable under neutral conditions upon heating to 130°C for 6 h but undergoes complete racemization within 10 h in the presence of stoichiometric amounts of a guanidine base at room temperature. The racemization is likely to proceed via formation of an achiral keteniminate intermediate and obeys reversible first‐order reaction kinetics with a half‐life time of 87.7 min in ethanolic hexanes at 23.2°C. Racemization is significantly slower and occurs with a half‐life time of 23.1 h at 22.4°C when the guanidine is replaced with a weaker amidine base. [ABSTRACT FROM AUTHOR]

In this study, a heart-cutting two-dimensional liquid chromatography (2D-LC) method for the determination of intracellular 2-hydroxyglutarate (2-HG) enantiomers is proposed. D-2-HG is an oncometabolite produced by tumors harboring isocitrate dehydrogenase (IDH) mutations. Hence, achieving accurate quantification of the 2-HG enantiomers in cancer cells is important. In this study, a fluorescence derivatization reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), was used. We found that 2-HG was successfully derivatized with NBD-PZ after lactonization. The enantiomers of 2-HG derivatized with NBD-PZ were quantified using the heart-cutting 2D-LC method. NBD-PZ-2-HG was stable for 1 week and was separated from endogenous compounds using an octadecyl silica column before enantiomeric separation on a chiral column. The developed heat-cutting 2D-LC method was validated and successfully applied to cell samples. The amount of D-2-HG and L-2-HG in U937 cells were 9.8 and 8.3 pmol/5.0 × 105 cells, respectively. Furthermore, high amounts of D-2-HG were measured in U937 cells expressing mutant IDH proteins as expected. This method can therefore be applied to further elucidate the role of 2-HG in cancer cells, particularly those harboring isocitrate dehydrogenase mutations.

Multi‐ingredient pre‐workout supplements (MIPS) contain Citrus aurantium as a source of bioactive amines such as p‐synephrine, but concerns regarding the authenticity of ingredients in some supplements as well as adverse effects from consumption have been raised. R‐(−)‐Synephrine is the predominant enantiomer in Citrus aurantium extracts while synthetic preparations are often racemic. The aims of this study were to develop a screening method to determine the ratio of synephrine enantiomers in pre‐workout supplements listing Citrus aurantium and to assess the ingredient authenticity by directly comparing their ratios to that found in Citrus aurantium standardised reference materials (SRMs). Quantification of enantiomers in the supplements and SRMs was achieved using a validated, high‐performance liquid chromatography‐single quadrupole mass spectrometry (HPLC‐UV‐QDa) direct enantioseparation method with a cellobiohydrolase (CBH) column (100 × 4.0 mm, 5 μM) and UV detection at 225 nm. Citrus aurantium SRMs were found to have an average enantiomeric ratio of 94:6 (R:S) with total synephrine ranging from 5.7 to 90.2 mg/g. Within the pilot sample of pre‐workout supplements tested, only 42% (5/12) had enantiomeric ratios consistent with the SRMs with total synephrine ranging from 0.03 to 91.2 mg/g. For the remaining supplements, four had racemic ratios of synephrine (0.14 to 5.4 mg/g), two lacked any detectable levels of synephrine, and one had solely the S‐(+)‐enantiomer (0.15 mg/g). These results bring the authenticity of labelling of some pre‐workout supplements into question and highlight the need for more stringent labelling regulations and testing for dietary supplements. [ABSTRACT FROM AUTHOR]

The series of C2-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6′-diiodo-2,2′,4,4′-tetramethylbiphenyl-3,3′-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity.

Density functional theory (DFT) calculations were made to investigate the interaction between enantiomers of methoxetamine (R & S) and achiral organic reagents, such as oxalate, succinate, fumarate, maleate, glutarate, adipate, pimelate, and suberate anions. The obtained results indicate that the oxalate and maleate anions have a greater ability to form conglomerate crystal of methoxetamine in the gas phase and in solution with chloroform, ethanol, and water. Results of the energy analysis reveal that, in comparison to gas phase and chloroform, the Gibbs energy, enthalpy, and internal thermal energy become more positive in the presence of water and ethanol solvents, confirming the negative effect of solvent polarity on enantiomer separation. It should also be noted that the presence of carbon-chain lengths greater than 3 atoms in organic reagents is not suitable for enantiomer separation and conglomerate crystal formation.. [ABSTRACT FROM AUTHOR]

In this study, a novel hydroxypropyl‐γ‐cyclodextrin (HP‐γ‐CD) functionalized monolithic capillary column was prepared by one‐pot sequential strategy and used for chiral separation in capillary electrochromatography for the first time. In one pot, GMA‐HP‐γ‐CD as functional monomer was allowed to be formed via the ring opening reaction between HP‐γ‐CD and glycidyl methacrylate (GMA) catalyzed by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) and then copolymerized directly with ethylene dimethacrylate (EDMA) and 2‐acrylamido‐2‐methyl propane sulfonic acid (AMPS) in the presence of porogenic solvents via thermally initiated free radical polymerization. The preparation conditions of monoliths were optimized. Enantiomer separations of six chiral drugs including pindolol, clorprenaline, tulobuterol, clenbuterol, propranolol, and tropicamide were achieved on the monolith. Among them, pindolol, clorprenaline, and tropicamide were baseline separated with resolution values of 1.62, 1.73, and 1.55, respectively. The mechanism of enantiomer separation was discussed by comparison of the HP‐γ‐CD and HP‐β‐CD functionalized monoliths. [ABSTRACT FROM AUTHOR]

In this work, brush-type chiral stationary phases (CSPs) with O-9-(2,6-diisopropylphenylcarbamoyl)-modified quinidine (DIPPCQD-brush/-SH) and O-9-(2,6-diisopropylphenylcarbamoyl)-modified quinine (DIPPCQN-brush/-SH) were prepared as benchmarks for comparison with new corresponding polymeric CSPs with more stable bonding chemistry. These polymeric CSPs were prepared by coating a thin poly(3-mercaptopropyl)-methylsiloxane film together with the chiral selector onto vinyl-modified silica. In a second step, immobilization of the quinine/quinidine derivatives as well as cross-linking of the polysiloxane film to the vinyl-silica is achieved by a double thiol-ene click reaction. The polymeric CSPs exhibited similar enantioselectivity as the corresponding brush phases, but showed lower chromatographic efficiencies. Chiral acidic substances were separated into enantiomers (e.g., N-protected amino acids, herbicides like dichlorprop) in accordance with an enantioselective anion-exchange process. Oxidation of residual thiol groups of the polymer DIPPCQN-CSP introduced sulfonic acid co-ligands on the silica surface, which resulted in greatly reduced retention times. Acting as immobilized counterions, they allowed to reduce the concentration of counterions in the mobile phase, which is favorable for liquid chromatography (LC)-electrospray ionization-mass spectrometry application. Ibuprofen showed a single peak under ambient column temperature. However, application of cryogenic cooling of the column enabled to achieve baseline separation at -20°C column temperature. It can be explained by an enthalpically dominated separation, which leads to an increase in separation factors when the temperature is reduced. While it is quite uncommon to work at subzero degree column temperature, this work illustrates the potential to exploit such temperature regime for optimization of LC enantiomer separations., (© 2023 The Authors. ELECTROPHORESIS published by Wiley‐VCH GmbH.)

Novel chiral selectors based on 3,5‐dimethyl phenylcarbamoylated β‐cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5‐dimethyl phenylcarbamoylated β‐cyclodextrin (β‐CD) chiral stationary phase (CSP) and 9‐O‐(tert‐butylcarbamoyl)‐QN‐based CSP (QN‐AX). Fmoc‐protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD‐based CSP and QN/QD‐based CSPs have broader application range than β‐CD‐based CSP or QN/QD‐based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc‐amino acids accompanied by the synergistic effect of β‐CD moiety, which lead to the different enantioseparation of β‐CD‐QN‐based CSP and β‐CD‐QD‐based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin‐based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β‐CD‐based CSP for certain samples. [ABSTRACT FROM AUTHOR]

Ramosetron is an enantiopure active pharmaceutical ingredient marketed in Japan since 1996 and later in a few Southeast Asian countries predominantly as an antiemetic for patients receiving chemotherapy. In this study, a simple and rapid high‐performance liquid chromoatography method for the separation of ramosetron and its related enantiomeric impurity by using hydrophilic interaction liquid chromatography mode is presented. Chiral resolution was performed on an analytical column (100 mm × 4.6 mm id) packed with 3 μm particles of cellulose‐based Chiralpak IC‐3 chiral stationary phase. Using a mobile phase containing acetonitrile–water–diethylamine (100:10:0.1, v/v/v) and setting the column temperature at 35°C, the resolution value was 7.35. At a flow rate of 1 mL/min, the enantioseparation was completed within 5 min. The proposed method was partially validated and it has proven to be sensitive with limit of detection and limit of quantitation of the (S)‐enantiomer impurity of 44.5 and 133.6 ng/mL. [ABSTRACT FROM AUTHOR]

Keywords: Chiral stationary phase; Enantiomer separation; Thyroxine; UPLC-MS/MS EN Chiral stationary phase Enantiomer separation Thyroxine UPLC-MS/MS 563 566 4 05/26/20 20200501 NES 200501 Enantioseparation of thyroxine using chiral crown ether type column. In positive ion electrospray UPLC-MS/MS for the discrimination of the thyroxine enantiomers, 80% MeOH/water (v/v) containing 0.07% trifluoroacetic acid (TFA) was used as an optimized mobile phase. This developed chiral UPLC-MS/MS method was applied for the determination of the enantiomeric purity of commercially available l-thyroxine analytes (three suppliers) and four pharmaceutical formulations of levothyroxine sodium tablets. [Extracted from the article]

Metabolomics profiling using liquid chromatography-mass spectrometry (LC-MS) has become an important tool in biomedical research. However, resolving enantiomers still represents a significant challenge in the metabolomics study of complex samples. Here, we introduced N,N-dimethyl-l-cysteine (dimethylcysteine, DiCys), a chiral thiol, for the o-phthalaldehyde (OPA) derivatization of enantiomeric amine metabolites. We took interest in DiCys because of its potential for multiplex isotope-tagged quantification. Here, we characterized the usefulness of DiCys in reversed-phase LC-MS analyses of chiral metabolites, compared against five commonly used chiral thiols: N-acetyl-l-cysteine (NAC); N-acetyl-d-penicillamine (NAP); isobutyryl-l-cysteine (IBLC); N-(tert-butoxycarbonyl)-l-cysteine methyl ester (NBC); and N-(tert-butylthiocarbamoyl)-l-cysteine ethyl ester (BTCC). DiCys and IBLC showed the best overall performance in terms of chiral separation, fluorescence intensity, and ionization efficiency. For chiral separation of amino acids, DiCys/OPA also outperformed Marfey’s reagents: 1-fluoro-2-4-dinitrophenyl-5-l-valine amide (FDVA) and 1-fluoro-2-4-dinitrophenyl-5-l-alanine amide (FDAA). As proof of principle, we compared DiCys and IBLC for detecting chiral metabolites in aqueous extracts of rice. By LC–MS analyses, both methods detected twenty proteinogenic l-amino acids and seven d-amino acids (Ala, Arg, Lys, Phe, Ser, Tyr, and Val), but DiCys showed better analyte separation. We conclude that DiCys/OPA is an excellent amine-derivatization method for enantiomeric metabolite detection in LC-MS analyses.

A highly-selective three-dimensional high-performance liquid chromatographic (3D-HPLC) system was developed for the determination of serine (Ser), threonine (Thr) and allo-threonine (aThr) enantiomers in human plasma to screen the new biomarker of chronic kidney disease (CKD). d-Ser has been reported to be the candidate biomarker of CKD, however, multiple biomarkers are still required. Therefore, Ser analogs of hydroxy amino acids are the focus in the present study. For the sensitive analysis, the amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole and detected by their fluorescence. The 3D-HPLC system consisted of a reversed-phase column (Singularity RP18, 1.0 × 250 mm), an anion-exchange column (Singularity AX, 1.0 × 150 mm) and a Pirkle-type chiral stationary phase (Singularity CSP-013S, 1.5 × 250 mm). The developed method was validated and applied to the human plasma samples obtained from 15 healthy volunteers and 165 CKD patients. The concentrations of the d-forms were 1.13-2.26 (Ser), 0.01-0.03 (Thr) and 0.04-0.10 μM (aThr) for the healthy volunteers and 0.95-19.0 (Ser), 0-0.57 (Thr) and 0.04-1.02 μM (aThr) for the CKD patients. The concentrations and the %d values of all the target d-amino acids were increased along with the decreasing of renal function and further investigation for clinical applications are expected., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In the present study, we aimed to optimize the synthesis stages of S-pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), a well-known anticonvulsant drug. We used appropriate solvents and compounds to reach a straightforward and applicable method. The advantages of this research were avoiding use of expensive and environment pollutant reagents and solvents, and also using a recoverable reagent. Discarding prevention of the intermediates and reagents besides attaining a higher yield of the obtained product were the additional achievements. All structures were characterized by FT-IR, 1H NMR, and the purity of S-pregabalin was evaluated using the HPLC assay. [ABSTRACT FROM AUTHOR]

Liquid chromatographic enantiomer separation and simultaneous determination of chemical and enantiomeric purity of α‐amino acids and their methyl esters as N‐fluorenylmethoxycarbonyl (FMOC) derivatives was performed on three covalently bonded type chiral stationary phases (CSPs) derived from amylose derivatives. The enantiomer separation of α‐amino acid esters as N‐FMOC derivatives was better than that of the corresponding acids, especially for CSP 1 and 2. Chemical impurities as the corresponding racemic acids present in several commercially available racemic amino acid methyl esters were observed to be 0.49–17.50%. Enantiomeric impurities of several commercially available L‐amino acid methyl esters were found to be 0.03–0.58%, whereas chemical impurities as the corresponding racemic acids present in the same analytes were found to be 0.13–13.62%. This developed analytical method will be useful for the determination of chemical and enantiomeric purity of α‐amino acids and/or esters as N‐FMOC derivatives using amylose‐derived CSPs. [ABSTRACT FROM AUTHOR]

• Chiral analysis method for underivatized hydroxy acids using capillary electrophoresis. • Baseline chiral resolution for all aliphatic and aromatic α- and β‑hydroxy acids. • Baseline chiral resolution for most polyhydroxy acids (e.g. DL-gluconic acid). • Migration patterns for all hydroxy acid enantiomers and stereoisomers investigated. • Applications for the analysis of complex matrices of hydroxy acid stereoisomers. Hydroxy acids (HAs) are ubiquitous in nature and play significant roles in various industrial and biological processes. Most HAs harbor at least one chiral center, therefore the development of efficient chiral analysis techniques for HA stereoisomers is of crucial importance across a wide range of fields. A capillary electrophoresis (CE) method was developed for the chiral analysis and quantification of aliphatic and aromatic α‑hydroxy acid (AHA) enantiomers, aliphatic β‑hydroxy acid (BHA) enantiomers and aliphatic polyhydroxy acid (PHA) stereoisomers. Using a modified partial filling-counter current method with indirect UV detection, high resolution (Rs) was achieved with vancomycin as a chiral selector added to the background electrolyte composed of 10 mM of benzoic acid/L-histidine at pH 5 using a polyacrylamide-coated capillary. This method could be readily applied to the determination of the enantiomers of 12 aliphatic AHAs, 4 aromatic AHAs, 3 aliphatic BHAs, as well as to the determination of the stereoisomers of tartaric acid, 2,3-dihydroxybutanoic acid, 2,3,4,5-tetrahydroxypentanoic acid, and 2,3,4,5,6-pentahydroxyhexanoic acid without the need for sample derivatization. Finally, our study provides a robust and versatile strategy for the chiral and stereoselective analysis of a broad range of hydroxy acid compounds. [ABSTRACT FROM AUTHOR]

• Self-disproportionation of enantiomers (SDE) on a silica column was examined. • Isotherm coefficients were correlated with the modifier concentration. • Gradient elution allowed enhancement of SDE and separation selectivity. • Dynamic model was formulated and used to predict the process. The influence of mobile phase composition on the efficiency of enantiomer separation by achiral chromatography (ACh) was investigated. The separation was induced by the phenomenon of self-disproportionation of enantiomers (SDE) triggered by their homo and hetero-chiral interactions in an achiral environment. Typically, SDE occurs in apolar mobile phases of weak elution strength, which causes the separation time to extend and the process productivity to deteriorate. To mitigate that effect, we altered the content of a strong solvent (modifier) in the mobile phase by use of a solvent gradient in which the target enantiomer was separated in the presence of the weak solvent, whereas the unresolved mixture of enantiomers was eluted by increasing the modifier content in the mobile phase. This enabled accelerating the solute elution while preserving the separation selectivity. The approach was examined for the separation of nonracemic mixtures of two structurally different compounds that exhibited the SDE effect in ACh, i.e., metalaxyl (MX) and methyl p -tolyl sulfoxide (MTSO). The target compound of the separation was the more abundant enantiomer in the enantiomeric mixture. The process realization was preceded by the determination of the effect of the modifier content on the separation yield for enantiomeric mixtures of MX and MTSO of different enantiomeric excess (ee). In the case of MX, yield of the pure target enantiomer varied from 2 %, for the maximum concentration of the modifier, to 45 % for the minimum modifier concentration and the largest ee used in the experiments. In the case of MTSO, the yield varied from minimum 40 % to maximum 66 %. To predict the process, we employed a dynamic model, in which underlying thermodynamic dependencies were implemented. [ABSTRACT FROM AUTHOR]

Twelve new azole compounds were synthesized through an ene reaction involving methylidene heterocycles and phenylmaleimide, producing four oxazoles, five thiazoles, and one pyridine derivative, and ethyl glyoxylate for an oxazole and a thiazole compound. The twelve azoles have a stereogenic center in their structure. Hence, a method to separate the enantiomeric pairs, must be provided if any further study of chemical and pharmacological importance of these compounds is to be accomplished. Six chiral stationary phases were assayed: four were based on macrocyclic glycopeptide selectors and two on linear carbohydrates, i.e., derivatized maltodextrin and amylose. The enantiomers of the entire set of new chiral azole compounds were separated using three different mobile phase elution modes: normal phase, polar organic, and reversed phase. The most effective chiral stationary phase was the MaltoShell column, which was able to separate ten of the twelve compounds in one elution mode or another. Structural similarities in the newly synthesized oxazoles provided some insights into possible chiral recognition mechanisms.

Chiral nanoporous solids are a fascinating class of materials, allowing efficient enantiomer separation. Here, we review the status, applications, and potential of thin films of homochiral metal–organic frameworks (MOFs). Combining the advantages of MOFs, whose well-defined, crystalline structures can be rationally tuned, with the benefits of thin films enables new opportunities for the characterization of the enantioselectivity, e.g., via chiroptical spectroscopy and straightforward molecular uptake quantifications. By incorporating photoresponsive molecules in the chiral MOF films, the enantioselectivity of the material can be dynamically remote-controlled. The most promising application of MOF films is their use as membranes, where the enantioselective separation of chiral molecules is demonstrated and parameters for further improvements are discussed.

Enantiomers typically show different pharmacological, toxicological, and physiological properties. Thus, the preparation of enantiopure compounds is of great significance for human health and sustainable development. Compared with asymmetric catalysis, enantiomeric separation is simpler, faster, and more efficient; as such, it has become the preferred method for obtaining pure enantiomers. At present, enantiomeric separation methods mainly include chromatography, nanochannel membrane separation, selective adsorption, and recrystallization. In particular, gas chromatography (GC) plays an important role in enantioseparation because of its high sensitivity, excellent reproducibility, and outstanding processing capacity for various enantiomers. The stationary phase is key to the separation efficiency of GC, and more efficient, stable, and cost-effective materials that could serve as stationary phases are constantly being explored. Organic frameworks, such as covalent organic frameworks (COFs), metal-organic frameworks (MOFs), porous organic cages (POCs), metal-organic cages (MOCs), and hydrogen-bonded organic frameworks (HOFs), possess large specific surface areas, high porosities, tunable pore sizes, and easy functionalization, rendering them promising candidates for the separation of mixed analytes. Research has shown that the use of organic frameworks as stationary phases for GC results in excellent column efficiency and high resolution for various analytes, including n -alkanes, n -alcohols, polycyclic aromatic hydrocarbons, positional isomers, and organic fluorides. Furthermore, organic frameworks can be prepared as chiral stationary phases for GC by the intelligent introduction of a chiral moiety, thereby enabling the efficient separation of enantiomers. Synthetic strategies for chiral organic frameworks are primarily categorized as post-synthesis or bottom-up approaches. In general, the post-synthesis strategy can introduce various chiral sites to the framework; however, the distribution of chiral sites may not be uniform, and the ordered framework may be destroyed during the post-synthesis process. The bottom-up strategy allows for the uniform and precise distribution of chiral sites in the framework, but the synthesis of chiral monomers and the constraint between asymmetry and crystallinity limit its development. Chiral induction has been proposed as an alternative strategy for synthesizing chiral organic frameworks. The use of this strategy has led to the successful preparation of organic frameworks with abundant chiral sites and excellent crystallinity. Dynamic coating and in situ growth are the main approaches used to transform the as-prepared chiral organic frameworks into stationary phases. Notably, the in situ growth approach can yield chiral COF/MOF-coated capillary columns that provide high resolution for the separation of enantiomers with excellent repeatability and reproducibility. Nevertheless, owing to the slightly complex pretreatment process and the difficulty of synthesizing chiral organic frameworks, the in situ growth approach has not yet been widely applied. Owing to their excellent solvent processing performance, POCs, MOCs, and HOFs can be easily coated on the inner walls of columns to form membranes via dynamic or static coating. A series of enantiomers have been successfully separated and analyzed by immobilizing chiral COFs, MOFs, POCs, MOCs, and HOFs on GC capillary columns, demonstrating the great potential of chiral organic frameworks for enantiomeric separation. In general, the mechanisms by which chiral organic frameworks recognize enantiomers could be mainly categorized as van der Waals interactions, hydrogen bonding, π - π interactions, and size-exclusion effects. While molecular simulations can offer some insights into these recognition mechanisms, clarifying these mechanisms based on effective characterization remains challenging. In summary, organic frameworks show outstanding advantages for enantiomer separation. Given breakthroughs in synthetic strategies for chiral organic frameworks and the in-depth study of chiral recognition mechanisms, chiral organic frameworks may be expected to become an important aspect in the field of chiral materials, further realizing the large-scale analysis and production of chiral analytes. A total of 64 references, most of which are from the American Chemical Society, Springer Nature, Wiley Online Library, and Elsevier databases, are cited in this review.

This review mainly highlights our studies on the synthesis of one-handed helical polymers with a static memory of helicity based on the noncovalent helicity induction with a helical-sense bias and subsequent memory of the helicity approach that we developed during the past decade. Apart from the previous approaches, an excess one-handed helical conformation, once induced by nonracemic molecules, is immediately retained ("memorized") after the complete removal of the nonracemic molecules, accompanied by a significant amplification of the asymmetry, providing novel switchable chiral materials for chromatographic enantioseparation and asymmetric catalysis as well as a highly sensitive colorimetric and fluorescence chiral sensor. A conceptually new one-handed helix formation in a racemic helical polymer composed of racemic repeating units through the deracemization of the pendants is described.

A liquid chromatographic chiral stationary phase, which contains two N–CH3 amide connecting groups, based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid was first applied to the resolution of methoxyphenamine (2‐methoxy‐N‐methylamphetamine, a β‐adrenergic receptor agonist used as a bronchodilator). The resolution of methoxyphenamine on the chiral stationary phase containing two N–CH3 amide connecting groups was quite successful with the separation factor (α) of 1.42 and resolution (RS) of 4.22 compared with those (α of 1.09 and RS of 1.55) on the chiral stationary phase containing two N–H amide connecting groups. In addition, the chiral stationary phase containing two N–CH3 amide connecting groups was applied to the resolution of methoxyphenamine analogues. From the comparison of the resolution results of methoxyphenamine with those of methoxyphenamine analogues on the chiral stationary phase containing two N–CH3 amide connecting groups, the N‐methyl group and the 2‐methoxyphenyl group of methoxyphenamine were elucidated to be the structurally essential parts for the resolution on the chiral stationary phase. [ABSTRACT FROM AUTHOR]

In this study, the retention properties of the immobilized polysaccharide‐derived Chiralpak IG‐3 chiral stationary phase under aqueous‐organic conditions were investigated. A systematic evaluation of the retention factors of the enantiomers of the chiral sulfoxide oxfendazole, endowed with anthelmintic activity and selected as test compound, was carried out changing progressively the water content in hydro‐organic eluents containing methanol, ethanol or acetonitrile. From the results obtained with acetonitrile/water mobile phases and the associated retention plots, clear U‐shape retention dependencies, indicative of the interplay of both hydrophilic interaction liquid chromatography and reversed‐phase modes, were highlighted. A U‐turn point of retention mechanism was recorded in correspondence of the acetonitrile/water 100:40 v/v mobile phase. Retention was significantly affected by small percentages of trifluoroacetic acid or diethylamine additives incorporated in the mobile phase. It is worth emphasizing that the basic additive was more effective in reducing retention in the reversed‐phase region, while the action of acid additive was more pronounced in the hydrophilic interaction liquid chromatography region. Finally, either in the transition from hydrophilic interaction liquid chromatography to reversed‐phase conditions or after additive addition, the enantioselectivity did not vary significantly. [ABSTRACT FROM AUTHOR]

Highlights • 2D HPLC-MS/MS enables specific assay for chiral amino acids. • Enantiomers of Ala, Asp, Glu, Leu, Pro and Ser were determined. • Trace levels of d -Ala, d -Pro and d -Ser were clearly determined in human plasma. • d -Forms of all target amino acids were found in human urine without interference. Abstract An automated two-dimensional HPLC-MS/MS system was designed and developed for the highly selective determination of trace levels of d -amino acids. As the targets, frequently observed ones in mammalian physiological fluids, Ala, Asp, Glu, Leu, Pro and Ser, were selected because these d -amino acids are the potential biomarkers for the early and sensitive diagnoses of various diseases. The target analytes were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), then isolated by a reversed-phase column in the first dimension. The NBD-amino acid fractions were automatically collected into the multi-loop device, and introduced into the enantioselective column in the second dimension to separate the d - and l -forms followed by detection by an MS/MS. The obtained resolution values of the enantiomers were 1.87–5.17 and the calibration lines, precision and accuracy were practically sufficient. By using the present 2D HPLC-MS/MS system, trace levels of d -amino acids in complex biological matrices were determined without disturbance by the intrinsic interfering compounds, and successfully applied to the analysis of the human clinical samples (plasma and urine). [ABSTRACT FROM AUTHOR]

As the understanding of the various biological actions of compounds with different stereochemistry has grown, the necessity to develop methods for the analytical qualification and quantification of chiral products has become particularly important. The last quarter of the century has seen a vast growth of diverse chiral technologies, including stereocontrolled synthesis and enantioselective separation and analysis concepts. By the introduction of covalently bonded silica-based chiral stationary phases (CSPs), the so-called direct liquid chromatographic (LC) methods of enantiomer separation became the state-of-the-art methodology. Although a large number of CSPs is available nowadays, the design and development of new chiral selectors and CSPs are still needed since it is obvious that in practice one needs a good portfolio of different CSPs and focused “chiral columns” to tackle the challenging tasks. This review discusses and summarizes direct enantiomer separations of chiral acids and ampholytes applying anionic and zwitterionic ion-exchangers derived from Cinchona alkaloids with emphasis on literature data published in the last 10 years. Our aim is to provide an overview of practical solutions, while focusing on the integration of molecular recognition and methodological variables. [ABSTRACT FROM AUTHOR]

Normal phase (NP) high-performance liquid and sub- and supercritical fluid chromatographic (both acronymed as SFC) methods have been developed for the enantiomer separation of three basic and three ampholytic structurally related C-3-substituted indole analogs on seven non-ionic (neutral) polysaccharide-based and two chemically entirely different zwitterionic Cinchona alkaloid- and sulfonic acid-based chiral stationary phases (CSPs). In a systematic fashion the effect of the composition of the mobile phase, the nature of the alcohol and amine additives on the retention characteristics and enantioselectivity of the ionizable analytes were investigated. On all studied polysaccharide-based CSPs the three ampholytes remained unretained in NP-LC mode, while they were nicely retained and resolved in SFC mode. These unexpected results underline a specific property of liquid CO 2 as bulk solvent in combination with alcohols as co-solvents and amine additives thus creating an environment around the chiral selector sites which support the retention of ampholytes. The zwitterionic CSPs worked equally well for the resolution of the basic and ampholytic analytes using a polar ionic mobile phase in both LC and SFC modes. Results acquired by studying the effect of temperature were used to calculate the changes in standard enthalpy Δ ( ΔH °), entropy Δ ( ΔS °), and free energy Δ ( ΔG °) applying van't Hoff plots. The values of the thermodynamic parameters depended on the nature of selectors, the structure of analytes and the properties of the mobile phases. On polysaccharide-based CSPs and columns operated in NP-LC mode enthalpically-, whereas in SFC mode both enthalpically- and entropically-driven enantiomer separations were observed. [ABSTRACT FROM AUTHOR]

N -Methoxycarbonyl chitosan was prepared by selectively modifying the amino group at the 2-position of chitosan with methyl chloroformate, which was further functionalized with p -methylbenzylamine to produce chitosan ( p -methylbenzylurea). Then, the hydroxyl groups at the 3- and 6-positions of the glucose skeleton were modified with various phenyl isocyanates, affording a series of chitosan 3,6-bis(arylcarbamate)-2-( p -methylbenzylurea)s, which were characterized and proposed as chiral selectors for enantiomer separation. Nineteen racemates, most of which are drugs or intermediates for drugs, were selected as the model analytes to evaluate the enantioseparation performance. The structure-performance relationship of the chiral selectors was investigated in detail. It was found that the methyl-substituted chiral selectors possessed more preferable enantioseparation performance compared with the chloro-substituted ones, and the chiral selectors containing a methyl substituent at the 4-position of the benzene ring showed the best chiral recognition and separation ability with 17 racemates being recognized and 13 racemates being baseline separated. The prepared chiral separation materials derived from these chiral selectors exhibited favorable solvent tolerance towards ethyl acetate, acetone, chloroform and a low proportion of tetrahydrofuran in normal phase. To sum up, this work provided a useful reference for the design and preparation of high-performance chiral separation materials for efficient enantiomer separation. [ABSTRACT FROM AUTHOR]

Liquid chromatographic ligand-exchange chiral stationary phases (CSPs) have been developed for the resolution of racemic compounds, which can be used as bidentate or tridentate ligands. In this paper, we review the development of liquid chromatographic ligand-exchange CSPs based on amino alcohols or their derivatives coated dynamically on octadecylsilica gel or bonded covalently to silica gel and their applications to the resolution of α-amino acids, β-amino acids, α-hydroxycarboxylic acids and proton pump inhibitors (PPIs). The relationship between the structures of CSPs and chromatographic resolution behaviors is discussed. In particular, a rational approach to the development of improved ligand-exchange CSPs based on amino alcohols derived from α-amino acids is followed. [ABSTRACT FROM AUTHOR]

Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[ b ]thiophene-2-carboxylic acid ( 6 ). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the ( S) -configuration. The (−)-enantiomer, ORG20864, was therefore assigned the ( R) -stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance. [ABSTRACT FROM AUTHOR]

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro ( 55 , 56 , 61 , 64 , 66 , and 70 – 73 ) and in vivo ( 66 and 72 ) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei . Compounds 55 , 56 , 61 , 64 , 66 and 70 – 73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s < 0.28 μM), and compounds 55 , 56 , 64 , 70 , 71 , and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum , targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds. [ABSTRACT FROM AUTHOR]

Enantiomeric analysis of small molecules is important in many research fields, including in drug development. Here, chiral recognition of amino acid enantiomers using differential ion mobility spectrometry (DMS) mass spectrometry (MS) is demonstrated. Diastereomeric proton bound complexes were formed between enantiomers of amino acids (tryptophan and phenylalanine) and N - tert -butoxycarbonyl- O -benzyl- l -serine (BBS) by electrospray ionization for analysis by DMS-MS and collision-induced dissociation (CID). If the DMS resolution is sufficiently high, ionic diastereomers (as opposed to enantiomers) can in principle be separated without the use of a chiral gas. Peaks corresponding to the L - and D -enantiomers for both tryptophan and phenylalanine in the DMS-MS spectra were resolved by increasing the ratio of He in the carrier gas from 100% N 2 to 50:50 He:N 2 %. In contrast, CID spectra of the corresponding diastereomeric dimer complex ions were nearly identical, indicating that chiral recognition by CID was not possible under these conditions. For mixtures of L - and D -tryptophan, a linear calibration curve can be obtained by plotting the enantiomeric excess measured by DMS-MS vs. the known values in solution (slope of 1.000, intercept of −0.010 and R 2 of 0.997). That is, enantiopurity can be quantified using a separation process that occurs in milliseconds. Thus, DMS-MS analysis of proton bound diastereomeric dimers is a powerful approach for the rapid enantiomeric analysis of relatively small molecules. [ABSTRACT FROM AUTHOR]

The predominant enantiomer of nicotine found in nature is (S)-nicotine and its pharmacology has been widely established. However, pharmacologic information concerning individual enantiomers of nicotine-related compounds is limited. Recently, a modified macrocyclic glycopeptide chiral selector was found to be highly stereoselective for most tobacco alkaloids and metabolites. This study examines the semi-synthetic and native known macrocyclic glycopeptides for chiral recognition, separation, and characterization of the largest group of nicotine-related compounds ever reported (tobacco alkaloids, nicotine metabolites and derivatives, and tobacco-specific nitrosamines). The enantioseparation of nicotine is accomplished in less than 20 s for example. All liquid chromatography separations are mass spectrometry compatible for the tobacco alkaloids, as well as their metabolites. Ring-closed, cyclized structures were identified and separated from their ring-open, straight chain equilibrium structures. Also, E/Z-tobacco-specific nitrosamines and their enantiomers were directly separated. E/Z isomers also are known to have different physical and chemical properties and biological activities. This study provides optimal separation conditions for the analysis of nicotine-related isomers, which in the past have been reported to be ineffectively separated which can result in inaccurate results. The methodology of this study could be applied to cancer studies, and lead to more information about the role of these isomers in other diseases and as treatment for diseases. [ABSTRACT FROM AUTHOR]

Abstract: Two liquid chromatographic chiral stationary phases based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid were applied to the resolution of the amide derivatives of cyclic α‐amino acids including proline and pipecolic acid. Among the five amide derivatives of proline, aniline amide was resolved best on the first chiral stationary phase, which contains two N–H tethering amide groups, with the separation factor of 1.31 and the resolution of 2.60, and on the second chiral stationary phase, which contains two N–CH3 tethering amide groups, with the separation factor of 1.57 and the resolution of 5.50. Among the five amide derivatives of pipecolic acid, 2‐naphthyl amide was resolved best on the first chiral stationary phase with the separation factor of 1.30 and the resolution of 1.75, but 1‐naphthylmethyl amide was resolved best on the second chiral stationary phase with the separation factor of 1.30 and the resolution of 2.26. In general, the second chiral stationary phase was found to be better than the first chiral stationary phase in the resolution of the amide derivatives of cyclic α‐amino acids. In this study, the second chiral stationary phase was first demonstrated to be useful for the resolution of secondary amino compounds. [ABSTRACT FROM AUTHOR]

Abstract: In the enantiomeric separation of highly polar compounds, a traditionally challenging task for high‐performance liquid chromatography, ion‐exchange chiral stationary phases have found the main field of application. In this contribution, we present a series of novel anion‐exchange‐type chiral stationary phases for enantiomer separation of protected amino phosphonates and N‐protected amino acids. Two of the prepared selectors possessed a double and triple bond within a single molecule. Thus, they were immobilized onto silica support employing either a thiol‐ene (radical) or an azide‐yne (copper(I)‐catalyzed) click reaction. We evaluated the selectivity and the effect of immobilization proceeding either by the double bond of the Cinchona alkaloid or a triple bond of the carbamoyl moiety on the chromatographic performance of the chiral stationary phases using analytes with protecting groups of different size, flexibility, and π‐acidity. The previously observed preference toward protecting groups possessing π‐acidic units, which is a typical feature of Cinchona‐based chiral stationary phases, was preserved. In addition, increasing the bulkiness of the selectors’ carbamoyl units leads to significantly reduced retention times, while very high selectivity toward the tested analytes is retained. [ABSTRACT FROM AUTHOR]

Abstract: For the enantioselective and simultaneous analysis of lactate and 3‐hydroxybutyrate, a validated online two‐dimensional high‐performance liquid chromatography system using 4‐nitro‐7‐piperazino‐2,1,3‐benzoxadiazole as a fluorescent derivatization reagent has been developed. For the reversed‐phase separation in the first dimension, a Capcell Pak C18 ACR column (1.5 × 250 mm, particle size 3 μm) was used, and the target fractions were isolated by their hydrophobicity. In the second dimension, a polysaccharide‐coated enantioselective column, Chiralpak AD‐H (2.0 × 250 mm, 5 μm), was used. The system was validated by the calibration curve, intraday precision, interday precision, and accuracy using standards and real human samples, and satisfactory results were obtained. The present method was applied to human plasma and urine, and in the plasma, trace amounts of d‐lactate (8.4 μM) and l‐3‐hydroxybutyrate (1.0 μM), besides high levels of l‐lactate (860.9 μM) and d‐3‐hydroxybutyrate (59.4 μM), were successfully determined. In urine, trace levels of d‐lactate (3.7 μM), d‐3‐hydroxybutyrate (2.3 μM), and l‐3‐hydroxybutyrate (3.3 μM) in addition to a relatively large amount of l‐lactate (15.4 μM) were observed. The present online two‐dimensional high‐performance liquid chromatography system is useful for the simultaneous determination of all the lactate and 3‐hydroxybutyrate enantiomers in human physiological fluids, and further clinical applications are ongoing. [ABSTRACT FROM AUTHOR]

Amino acids normally have a chiral carbon and d / l -enantiomers are present. Due to the homochirality features on the present Earth, l -enantiomers are predominant in the living beings and the d -enantiomers are rare. Along with the progress and development of cutting edge analytical methods, several d -amino acids were found even in the higher animals including humans, and their biological functions and diagnostic values have also been reported. However, the amounts of these d -amino acids are much lower than the l -forms, and development/utilization of highly sensitive and selective methods are practically essential to avoid the disturbance from uncountable intrinsic substances. In the present review, multi-dimensional HPLC methods for the determination of chiral amino acids, especially two-dimensional LC-MS/MS and three-dimensional LC methods, and their applications to a variety of real-world matrices are summarized. • Two-dimensional LC-MS/MS and three-dimensional LC analysis of chiral amino acids were summarized. • Chiral amino acids were determined in mammalian, food/beverage samples. • Enzymatic regulation of D -amino acids in mammals were introduced. • Metabolic amino acids and related compounds were also analyzed. [ABSTRACT FROM AUTHOR]

• Carboxymethylated maltodextrin as an efficient chiral selector was synthesized. • It was synthesized through facile strategy by low cost and biocompatible materials. • It was used for enantiomer separation of basic drugs by capillary electrophoresis. • Cm-MD has high chiral separation efficiency in comparison with native MD. • The optimized CE method was used for quantification of enantiomers in tablets. In this work, carboxymethylated maltodextrin (Cm-MD) was successfully synthesized as an efficient anionic chiral selector and applied for the enantiomer separation of some basic drugs including tramadol, venlafaxine, verapamil, hydroxyzine, citalopram, fluoxetine, and amlodipine by capillary electrophoresis (CE). The synthesized chiral selector was characterized by the nuclear magnetic resonance and Fourier transform infrared spectrophotometry. Under the optimized Cm-MD modified CE conditions (background electrolyte: phosphate buffer (pH 5.0, 50 mM) containing 5% (w/v) Cm-MD; applied voltage: 20 kV; and capillary column temperature: 25 °C), successful enantiomer separation of all studied chiral drugs were observed. By comparison of Cm-MD and MD for enantiomer separation of the model drugs, it was revealed that Cm-MD exhibits a higher resolution in comparison to the MD modified CE. This enhanced resolution could be attributed to the electrostatic interactions between the cationic drugs and anionic Cm-MD and opposite direction mobility of the host-guest complex relative to the chiral analyte. The optimized Cm-MD modified CE method was successfully used for the assay of the enantiomers of citalopram and venlafaxine in commercial tablets. The proposed method showed the linear range of 5.0–150.0 mg/L and 10.0–150.0 mg/L for both enantiomers of citalopram and venlafaxine, respectively. The limits of quantification were 5.0 and 10.0 mg/L for the enantiomers of citalopram and venlafaxine, respectively. The limit of detection for all enantiomers was found to be < 3.0 mg/L. Intra- and inter-day RSDs (n = 4) were less than 9.7%. The relative errors were less than 9.4% for all enantiomers. The obtained results in this research show that Cm-MD as a new, efficient and inexpensive chiral selector can be used for enantiomer separation of basic drugs using the CE technique. [ABSTRACT FROM AUTHOR]

Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS) of 1.55 when a mobile phase consisting of methanol–acetonitrile–trifluoroacetic acid–triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition.

Chromatographic separation with solid stationary and fluid mobile phases is widely used to isolate and purify compounds. One of the most productive improvements in preparative chromatography is the simulated moving bed (SMB) process, which enables continuous feed supply and product removal by periodic operation of a multicolumn to simulate a countercurrent flow between the phases. The SMB process produces high-purity compounds, even with low selectivity, and offers higher productivity and lower eluent consumption than batch chromatography. Recently, intensive efforts have been made to expand the range of applications through the design, modeling, and optimization of the SMB process to produce advanced operating strategies, which are described and evaluated in this review. [ABSTRACT FROM AUTHOR]