Development Of Chiral Stationary Phases Research Articles

Chiral stationary phases and applications in gas chromatography.

Chiral compounds are ubiquitous in nature and play a pivotal role in biochemical processes, in chiroptical materials and applications, and as chiral drugs. The analysis and determination of the enantiomeric ratio (er) of chiral compounds is of enormous scientific, industrial, and economic importance. Chiral separation techniques and methods have become indispensable tools to separate chiral compounds into their enantiomers on an analytical as well on a preparative level to obtain enantiopure compounds. Chiral gas chromatography and high-performance liquid chromatography have paved the way and fostered several research areas, that is, asymmetric synthesis and catalysis in organic, medicinal, pharmaceutical, and supramolecular chemistry. The development of highly enantioselective chiral stationary phases was essential. In particular, the elucidation and understanding of the underlying enantioselective supramolecular separation mechanisms led to the design of new chiral stationary phases. This review article focuses on the development of chiral stationary phases for gas chromatography. The fundamental mechanisms of the recognition and separation of enantiomers and the selectors and chiral stationary phases used in chiral gas chromatography are presented. An overview over syntheses and applications of these chiral stationary phases is presented as a practical guidance for enantioselective separation of chiral compound classes and substances by gas chromatography.

Current trends in the development of polymer-based monolithic stationary phases.

This review focuses on the development and applications of organic polymer monoliths, with special attention to the literature published in 2021. The latest protocols in the preparation of polymer monoliths are discussed. In particular, tailored surface modification using nanomaterials, the development of chiral stationary phases and development of stationary phases for capillary electrochromatography are reviewed. Furthermore, the optimization of pore forming solvents composition is also discussed. Finally, the use of monolithic stationary phases in sample treatment using solid-phase extraction and enrichment methods, molecularly imprinted polymers and enzymatic reactors is mentioned.

Preparation and application of urea-based derivatized β-cyclodextrin chiral stationary phase based on diazotized silica microspheres

Recently, the design and development of efficient chiral stationary phases is still the core and goal of chiral chromatography. In order to quickly separate chiral drugs, we designed and prepared an environmentally friendly small particle chiral stationary phase: p-methylphenylurea-β-cyclodextrin chiral stationary phase (SiO2@PMPU-β-CD). Firstly, p-methylphenylurea-β-cyclodextrin (PMPU-β-CD) was connected to the surface of mesoporous silica microspheres by diazoresin (DR) to prepare a SiO2@PMPU-β-CD. In reverse elution mode, the column temperature was set at 25 °C, the flow rate was 0.2 mL/min, and ACNH2O (v/v = 70:30) was used as the elution condition of the mobile phase. The enantiomers of chlorpheniramine maleate, 2-phenylcyclohexanone, and promethazine were separated within 5 min. In addition, the addition of TEAA buffer to the mobile phase improved the enantiomer resolution of chlorpheniramine maleate from 1.03 to 5.69. The experimental results show that the SiO2@PMPU-β-CD column can be used for the separation of appellant chiral drugs with good repeatability, and the use of DR instead of silane coupling agent has the advantages of being non-toxic, environmentally protected, and easy to operate, which is of great significance for the development of chiral stationary phase.

Recent progress in the development of chiral stationary phases for high-performance liquid chromatography.

Separations and analyses of chiral compounds are important in many fields, including pharmaceutical production, preparation of chemical intermediates, and biochemistry. High-performance liquid chromatography using a chiral stationary phase is regarded as one of the most valuable methods for enantiomeric separation and analysis because it is highly efficient, is broadly applicable, and has powerful separation capability. The focus for development of this method is the identification of novel chiral stationary phases with superior recognition performance and good stability. The present article reviews recent progress in the development of new chiral stationary phases for high-performance liquid chromatography between January 2018 and June 2021. These newly reported chiral stationary phases are divided into three categories: small organic molecule-based (cyclodextrin and its derivatives, macrocyclic antibiotics, cinchona alkaloids, and other low molecular weight chiral molecules), macromolecule-based (cellulose and amylose derivatives, chitin and chitosan derivatives, and synthetic helical polymers) and chiral porous material-based (chiral metal-organic frameworks, chiral covalent organic frameworks, and chiral inorganic mesoporous silicas). Each type of chiral stationary phase is discussed in detail.

Hydroxypropyl-β-cyclodextrin encapsulated stationary phase based on silica monolith particles for enantioseparation in liquid chromatography.

Hydroxypropyl-β-cyclodextrin-encapsulated stationary phase incorporated on silica monolith particles was prepared by physical embedding, providing a new method for the development of chiral stationary phase for enantioseparation in liquid chromatography. Ground silica monolith particles of about 2.0μm were prepared via sol-gel reaction followed by differential sedimentation. Initially, the silica monolith particles were pretreated with 3-trimethoxysilyl propyl methacrylate to attach double-bonded ligands onto the surface, then a network structure was formed onto the surface of the particle using N-isopropyl acrylamide as functional monomer. Hydroxypropyl-β-cyclodextrin was encapsulated inside N-isopropyl acrylamide copolymerized layer on the surface of silica monolith particles. The effect of the amount of chiral selector on the chromatographic efficiency of the chiral stationary phase was examined. The glass lined stainless steel columns (1mm internal diameter, 300mm length) were packed with the stationary phase for estimation of the efficiency by separation of phenylsuccinic acid, oxybutynin, equol, and naproxen enantiomers in high-performance liquid chromatography, with the resolutions of 1.54, 1.72, 2.54, and 2.31, respectively. The column to column repeatabilities through relative standard deviation were found better than 3%. The experimental results indicate that the sol-gel ground silica particles modified with β-cyclodextrin provide a promising way for the separation of chiral enantiomers.

Chiral Stationary Phases for Liquid Chromatography Based on Chitin- and Chitosan-Derived Marine Polysaccharides

The development of chiral stationary phases (CSPs) for liquid chromatography (LC) revolutionized the enantioseparation and, nowadays, different types of CSPs are commercially available. Polysaccharide-based CSPs are one of the most versatile and widely used for both analytical and preparative applications and they are able to resolve several classes of racemates. Phenylcarbamates of amylose and cellulose derivatives are the most successful; however, polysaccharide-based CSPs comprising marine-derived polysaccharides are also described revealing high chiral recognition abilities and wider range of mobile phases. A literature survey covering the report on chitin and chitosan based CSPs is presented. The chemical structure of the chiral selectors, their development and applications in chiral LC are emphasized.

Enantiomeric Resolution of (RS)-Naproxen and Application of (S)- Naproxen in the Direct and Indirect Enantioseparation of Racemic Compounds by Liquid Chromatography: A Review.

(S)-Naproxen (Npx), an α-aryl propionic acid derivative, belongs to the class of Non-Steroidal Anti-Inflammatory Drugs and is easily available in pure (S)-form. (S)-Npx has been used as a chiral selector for chromatographic separation of a variety of racemates, using both direct and indirect methods, and has been found to be useful and successful as a basic chiral moiety. This review article describes methods for enantioseparation of (RS)-Npx, development of chiral stationary phases based on (S)-Npx and preparation of novel chiral derivatizing reagents synthesized from (S)-Npx along with their application for enantioseparation of several pharmaceutically important racemates.

Determination of Enantioselectivities by Means of Chiral Stationary Phase HPLC in Order to Identify Effective Proline-Derived Organocatalysts

The pyrrolidine fragment is a privileged scaffold within chiral ligands employed in coordination complexes exhibiting catalytic activity in asymmetric reactions and, more recently, as enantioselective organocatalysts per se. Likewise, the employment of (S)-proline as starting material constitutes the most direct form to synthesize those chiral derivatives. Afterwards, a preliminary evaluation of the catalytic performance of proline-derived compounds consists of screening many prochiral substrates in well standardized model reactions such as Michael additions and Mannich reactions, with the aim of identifying “broad spectrum” catalysts for more complex synthetic applications. Therefore, a central part of this process involves the fast and direct measurement of enantioselectivities of optically active adducts. The growing development of chiral stationary phases and thus, the wide commercial availability of chiral columns have consolidated high performance liquid chromatography (HPLC) as the preferred technique to identify the most effective catalysts.

Synthesis and characterization of chitosan alkyl urea

Chitosan is a versatile material employed for various purposes in many fields including the development of chiral stationary phases for enantioseparation. Chitosan alkyl urea is a kind of intermediate used to prepare enantioseparation materials. In order to synthesize the intermediates, in the present work, a new way to prepare chitosan alkyl urea has been established: chitosan was first reacted with methyl chloroformate yielding N-methoxyformylated chitosan, which was then converted to chitosan alkyl urea through amine-ester exchange reaction. With a large excess of methyl chloroformate and primary amine of low stereohindrance, the amino group in chitosan could be almost completely converted to ureido group. The as-prepared chitosan alkyl urea derivatives were characterized by IR, 1H NMR, 13C NMR,1H-1H COSY and 1H-13C HSQC NMR spectra. The chemical shifts of hydrogen and carbon atoms of glucose unit were assigned. It was found that the degree of substitution was obviously lower if cyclopropyl amine, aniline, tert-butyl amine and diethyl amine were used as reactants for the amine-ester exchange reaction. The reason was explained with the aid of theoretical calculations.

Enantioresolution of Chiral Derivatives of Xanthones on Different Types of Liquid Chromatography Stationary Phases: A Comparative Study

Since the development of chiral stationary phases (CSPs), liquid chromatography has emerged as one of the most useful methods for analyses and preparation of enantiomerically pure bioactive compounds. However, the key for success of enantioseparation lies in the first place in the choice of a suitable CSP having enantioselectivity for the target enantiomers. Thus, this work describes a comparative study of resolution of seven chiral derivatives of xanthones (CDXs) on nine CSPs of different nature (four macrocyclic antibiotics, two Pirkle-type and three polysaccharide-based), under multimodal elution conditions. The polysaccharide-based CSPs have proved to be most suitable to separate this group of compounds, since all the CDXs were enantioseparated with excellent enantioselectivity and resolution. Six of the seven CDXs were separated on macrocyclic antibiotic-based CSPs, however with low enantioresolution. The Pirkle-type CSPs exhibited specificity on chiral discrimination behavior, presenting very high enantioselectivity for CDXs with aromatic group linked to the chiral moiety. This comparative study provides valuable information in the field of enantioresolution, and constitutes a useful background for subsequent studies of this important class of compounds. Keywords: Amylose tris-3, 5-dimethylphenylcarbamate, amylose tris-3, 5-dimethoxyphenylcarbamate, cellulose tris-3, 5- dimethylphenylcarbamate, chiral derivatives of xanthones, chiral stationary phases, chirality, chirobiotic R, chirobiotic T, chirobiotic TAG, chirobiotic V, enantiomerically pure, enantioresolution, enantioselectivity, liquid chromatography, Lphenylglycine, macrocyclic antibiotic, multimodal elution, Pirkle-type stationary phases, polysaccharide-based stationary phases, (S, S)-Whelk-O1.

Probing the chiral separation mechanism and the absolute configuration of malathion, malaoxon and isomalathion enantiomers by chiral high performance liquid chromatography coupled with chiral detector–binding energy computations

Chiral separation mechanism determination and absolute configuration assignment are fundamental to the development of chiral stationary phases (CSPs) and the evaluation of both the enantioselective bioactivity and fate of chiral compounds. This work investigated the process of chiral separation and the assignment of the absolute configurations of malathion, malaoxon, and isomalathion using chiral high performance liquid chromatography (HPLC) coupled with chiral detector–binding energy computations. Hydrogen bonding was found to be a very important factor in the chiral separation of isomalathion on Chiralpak AD, although it did not exhibit a significant effect on the chiral separation of malathion and malaoxon on Chiralcel OJ. Based on the sign of a chiral detector, the relationships between the cotton effect, optical dispersion and absolute configuration were established for individual enantiomers of malathion, malaoxon, and isomalathion. The elution orders of the enantiomers of malathion and malaoxon on Chiralcel OJ and the stereoisomers of isomalathion on Chiralpak AD predicted by binding energy computations were found to coincide precisely with those observed in the chiral separation experiments. The result suggests that binding energy computations can be used to assign the absolute configuration of the enantiomers of chiral compounds eluted on CSPs.

Chiral Drugs: Current Status of the Industry and the Market

The biological activity of chiral substances often depends upon their stereochemistry, since the living body is a highly chiral environment. A large percentage of commercial and investigational pharmaceutical compounds are enantiomers, and many of them show significant enantioselective differences in their pharmacokinetics and pharmacodynamics. The importance of chirality of drugs has been increasingly recognized, and the consequences of using them as racemates or as enantiomers has been frequently discussed in the pharmaceutical literature during recent years. Most of the chiral drugs are administered as racemates, despite the fact that the optical isomers of a racemic drug can exhibit different pharmacological profiles in living systems. These differences can be expressed in e.g. the affinity of the enantiomers for certain receptor subtypes or enzymes, distribution rates, their metabolism and excretion, in antagonistic actions relative to each other, or their toxicological properties. Obviously, the more chiral centres present in a (drug) molecule, the more complex the situation becomes. The origin of the discovery of the role of stereochemistry in biochemical environments dates back to the late 1850’s, when Pasteur reported the different destruction rates of dextro and levo ammonium tartrate by the mold Penicillium glaucum. In the conclusion of his observations, Pasteur wrote: “Most natural organic products, the essential products of life, are asymmetric and possess such asymmetry that they are not superimposable on their images.” For some reason, this knowledge of racemic organic compounds and racemisation seemed to be forgotten until the question of racemic compounds was raised by Ariens in the late 1980’s. He asked the question” why we in some cases have to give doses to the patient where half of the content has no effect or the opposite effect?”. After this rediscovery of stereochemistry, the regulatory authorities defined more strict requirements on drug discovery and chiral compounds. Besides the ethical reasons, the therapeutic benefit (efficacy and safety) and, in several instances, extension of the life cycle of drugs have been the motivation for developing single enantiomers. Single–enantiomer drug sales show a continuous growth worldwide and many of the topselling drugs are marketed as single enantiomers. In this context, there has been a rapid development of enantioselective synthetic methodologies, which have now reached a high degree of diversity and complexity. Simultaneously, this new trend produced a rapid increase in the demand for stereoselective separation techniques and analytical assays for precise determination of the enantiomeric purity of chiral compounds. The development of chiral stationary phases (CSPs) or chiral selectors for gas chromatography (GC), liquid chromatography (LC) and capillary electrophoresis (CE) rapidly opened a new dimension in the area of separation technologies. The business of developing single isomer drugs came about, because the chemical production methods used for pharmaceuticals often produced racemic mixtures of two enantiomers. In the case of thalidomide, it was shown that one enantiomer was responsible for efficacy and another for side effects. Worldwide, the market for chiral fine chemicals sold as single enantiomers was $6.63 billion in 2000 and is expected to grow at a rate of 13.2% annually, reaching $16.0 billion in 2007. The drug industry is the driving engine for this strong growth, accounting for 81.2% of the total, equal to an overall worth of $5.38 billion, in the year 2000. The remaining $1.25 billion is divided among Copyright © 2007 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services Iranian Journal of Pharmaceutical Research (2007), 6 (2): 73-74

Fases estacionárias quirais para cromatografia líquida de alta eficiência

The development of Chiral Stationary Phases (CSPs) for high performance liquid chromatography has been studied by various researches around the world, especially, since 1980. This simple interest has been transformed into a tool of great technological value for the industrial community and scholars in general providing the existence of several CSPs, which act through different mechanisms of chiral discrimination. This paper describes the main types of CSPs that are used for the resolution of the majority of chiral compounds.

40 Years of Supramolecular Chemistry

40 Years of Supramolecular Chemistry

Development of chiral stationary phases consisting of low-molecular-weight cellulose derivatives covalently bonded to silica gel

We prepared chiral supports whose chiral stationary phase (CSP), consisting of a low-molecular-weight cellulose derivative (degree ofpolymerization: 15), is covalently bonded to silica gel. The cellulose used asthe base material of the CSP was pre-hydrolysed with phosphoric acid before thecoupling reaction to unite a reducing terminal in the cellulose and anaminopropyl group on the surface of silanized silica. After substitutinghydroxyl groups in cellulose by using 3,5-dichlorophenyl isocyanate or phenylisocyanate, we tested the CSP thus obtained for its performance in chiralrecognition and found a wide range of chiral discrimination ability. We alsoconfirmed that an elution using ‘strong’ solvents as a mobile phasecould be achieved, which is difficult for the coated-type CSPs because themobile phase may dissolve the CSP. However, more enantiomeric mixtures showedlarger selectivity factors (α) when eluted on the coated-type CSPs thanonthe covalently bonded CSPs. A coated-type CSP consisting of thelow-molecular-weight cellulose phenylcarbamate, prepared as a control CSPsample, showed comparable performance with the commercial coated-type column(CHIRALCEL® OC), so the slightly poorer performance ofthe chemically bonded CSPs may be explained by the difficulty of the polymerconsisting of the CSPs in taking an optimal supermolecular structure requiredfor chiral recognition due to the fixation to the silica gel. The lowdegreeof polymerization may have an additional effect.

An artificial plastic receptor that discriminates axial asymmetry

An artificial plastic receptor that can discriminate axial asymmetry of optically active binaphthyldiamine derivatives was prepared by the ‘molecular imprinting’ technique. A light-radical polymerization in the presence of an axially asymmetric compound, ( R)-2,2′-bis-methylcarbonylamino-1,1′-binaphthyl (binaphthyldiamine bis-acetamide (BINADA-ac)) as a template molecule with methacrylic acid (MA) as a functional monomer, and ethyleneglycol dimethacrylate (EGDMA) as a crosslinker, at 4°C. The obtained polymer exhibited a superior enantioselectivity to the ( R)-enantiomer by HPLC analyses. This plastic receptor should recognize the template molecule with its shape and character of its functional groups. It should be useful in the development of chiral stationary phases for the optical resolutions of axially asymmetric compounds.

An Artificial Plastic Receptor That Discriminates Axial Asymmetry.

An artificial plastic receptor that can discriminate axial asymmetry of optically active binaphthyldiamine derivatives was prepared by the 'molecular imprinting' technique. A light-radical polymerization in the presence of an axially asymmetric compound, (R)-2,2'-bis-methylcarbonylamino-1,1'-binaphthyl (binaphthyldiamine bis-acetamide (BINADA-ac)) as a template molecule with methacrylic acid (MA) as a functional monomer, and ethyleneglycol dimethacrylate (EGDMA) as a crosslinker, at 4 degrees C. The obtained polymer exhibited a superior enantioselectivity to the (R)-enantiomer by HPLC analyses. This plastic receptor should recognize the template molecule with its shape and character of its functional groups. It should be useful in the development of chiral stationary phases for the optical resolutions of axially asymmetric compounds.

Chiral separation of enantiomers via selector/selectand hydrogen bondings

The progress made in the development of chiral stationary phases based on hydrogen-bonding selector/selectand associates is reviewed here. The structure of the different selectand/selector systems was established through X-ray diffraction and other spectroscopic techniques. The structure of the energetically more stable diastereomeric-associate was then correlated to the chromatographic results, namely to the elution order and the enantioselectivity of each of the systems. Chirality 10:382–395, 1998. © 1998 Wiley-Liss, Inc.

Development of chiral stationary phases for the enantiomeric resolution of dihydrodiols of polycyclic aromatic hydrocarbons by π-donor-acceptor interactions

Chiral stationary phases (CSPs) derived from ( R)-(−)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy) propionic acid (TAPA) covalently bound to silica gel have been developed by altering the alkyl group at the chiral centre or the number of aromatic rings and their degree of nitration. The chromatographic properties of the CSPs were characterized by use of a racemic model solute. Depending on the solvent strength of the mobile phase, the CSPs exhibit the quality of a normal or a reversed phase. The chromatographic behaviour of 30 racemic hydroxylated derivatives of polycyclic aromatic hydrocarbons (PAHs) on ( R)-(−)-TAPA CSP revealed the structural requirements for chiral recognition. The applicability of the CSPs for the enantiomeric separation of trans-dihydrodiols of PAHs on an analytical as well as preparative scale and for investigating the enantioselectivity of the biotransformation and genotoxicity of PAHs is demonstrated.

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

Abstract2,2,2‐Trifluoro‐(9‐anthryl)‐ethanol (TFAE) has been extensively used, in its pure enantiomeric forms, as a chiral solvating agent in nuclear magnetic resonance spectroscopy (NMR). It has also played an important role in the development of chiral stationary phases in liquid chromatography (LC). X‐ray crystallography of the enantiomeric and racemic crystals shows, in both cases, the formation of an intermolecular hydrogen bond between the OH and the π‐face of one of the rings of the anthracene aromatic system.1 Few examples of such hydrogen bonding have been published previously, and those that have are not as clear cut as in this case. An explanation for the hydrogen bonding is sought using molecular modelling via the PM3 analytically derived molecular electrostatic potentials. Using NMR and dynamic lineshape analysis, the barrier to rotation about the aryl‐carbon bond is estimated, indicating the CCF3 bond to be perpendicular to the anthracene axis in nonpolar solution. This conformation is identical to the conformation in the crystal. Evidence is also presented to support the formation of intermolecular π‐facial hydrogen bonding in TFAE solutions. It is thought that such hydrogen bonding may be implicated in chiral recognition using this compound. © 1994 Wiley‐Liss, Inc.