Application of thin-layer chromatography in enantiomeric chiral analysis-an overview

Several chiral drugs are produced and administered as pure enantiomers, whereas many others, especially of synthetic origin, are used mainly in the form of racemates. The biological and pharmacological activity of chiral compounds depends on their configuration. The racemic drugs may exhibit quite different activity from the optically pure drugs. Often only one of the enantiomers is pharmacologically active and/or even can be toxic. Since numerous enantiomers have been shown to behave differently from at least one point of view, whether pharmacokinetic, pharmacodynamic, toxicological or interaction, there seems to be hardly any exception to the general rule that a racemate cannot be considered as a single drug entity. A variety of chromatographic methods have been developed for optical resolution recently. Usually direct separation of the enantiomers is carried out on HPTLC chiral precoated plates or on plates impregnated with chiral substances. TLC techniques are a developing branch of separation and quantitation of drugs, both in pharmaceutical dosage forms and in biological material. This review presents an overview of the current successful enantioseparations of drugs by TLC and their potential in the analysis of the drug racemates.     

外消旋硫代缩水甘油醚在多糖基质手性柱上的手性拆分

在自行合成的3种多糖基质的手性固定相上直接拆分了7种外消旋硫代缩水甘油醚，初步探讨了手性化合物结构在手性识别过程中对手性拆分的影响，并对手性固定相的手性识别能力进行了评价。     

Synthesis of chiral building blocks for use in drug discovery

In the past decade there has been a significant growth in the sales of pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy. This in turn impacts on researchers involved in preclinical discovery work. Besides traditional chiral pool and resolution of racemates as sources of chiral building blocks, many new synthetic methods including a great variety of catalytic reactions have been developed which facilitate the production of complex chiral drug candidates for clinical trials. The most ambitious technique is to synthesise homochiral compounds from non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of the synthesis of chiral building blocks from achiral materials utilizing asymmetric hydrogenation and asymmetric epoxidation are presented.     

纤维素类手性固定相及高效液相色谱-旋光仪联用技术的研究

合成了3种纤维素衍生物并分别填充分析型色谱柱,研究了不同的涂敷条件对柱效的影响以及色谱柱的稳定性,对外消旋化合物进行了手性拆分。实现了高效液相色谱－旋光仪的联用,获得了在线旋光曲线。     

Enantioseparation of novel chiral tetrahedrane-type clusters on an amylose tris (Phenylcarbamate) chiral stationary phase

Summary Amylose tris(phenylcarbamate) (ATPC) coated on a small particle silica gel was prepared. This ATPC chiral stationary phase (ATPC-CSP) was found to be useful for the enantiomeric separation of some novel chiral tetrahedrane-type clusters. Moreover, the influence of mobile phase modifier and of the structure of chiral tetrahedrane-type clusters on the chiral separation and retention were investigated. The results suggest that not only the structure and concentration of alcohol in mobile phase, but also the subtle structural differences in racemates can have a pronounced effect on enantiomeric separation and retention.     

Chiral resolution of multichiral center racemates by different modalities of chromatography

It is a continuous chase of researchers to separate chiral racemates due to their dominance in the pharmaceutical industry, agrochemicals, and food additives. There are many analytical techniques which have been used to resolve one chiral center racemates, but, little the literature report is scanty for the resolution of multiple stereogenic center racemates. Therefore, in this article the efforts were made to describe the enantiomeric resolution of multiple stereogenic center racemates by different modalities of chromatography. The various modalities discussed are high-performance liquid chromatography, capillary electrophoretic chromatography, miceller electrokinetic chromatography, supercritical fluid chromatography, nanoliquid chromatography, and gas chromatography. Besides, the attempts have also been made to discuss the future challenges and prospectives of the enantiomeric resolution of multichiral racemates.     

Applications of Cellulose-Based Chiral Stationary Phases in the Resolution of Some Beta-Adrenoceptor Antagonists

Abstract

Cellulose tris (3,5-dimethylphenyl carbamate) known as Chiralcel OD chiral stationary phase (CSP) is one of the most commonly used cellulosic CSPs which have been successfully used for separation, enantiomeric purity determination and analysis of several drug racemates including β-adrenoceptor antagonists.

Resolution of timolol, penbutolol, celiprolol and carazolol enantiomers are achieved using this CSP. A possible chiral recognition mechanism(s) for these β-adrenergic blockers and this chiral stationary phase is presented.     

分子印迹薄层色谱手性固定相的制备及其色谱性能

分别以右旋扁桃酸、右旋邻氯扁桃酸和右旋对氯扁桃酸为模板,丙烯酰胺、乙二醇二甲基丙烯酸酯为功能单体和交联剂合成分子印迹聚合物,并以此作为薄层色谱手性固定相。研究了模板分子消旋体在手性固定相上的分离情况,并讨论了展开剂中乙酸含量对分离的影响。在乙腈-5%乙酸展开体系中扁桃酸、邻氯扁桃酸和对氯扁桃酸消旋体得到较好的分离,分离因子分别为1.45,1.62和1.56。该手性固定相对模板分子的结构类似物也具有一定的手性交叉分离能力。讨论了分析物的化学结构对该手性固定相识别性能的影响。该方法为快速、灵敏地对手性物质分析、定性提供了一条简便的途径。     

Simultaneous microbatch screening of enantiorecognition on solid chiral selectors using selected mixtures of test-racemates: a case study on cellulose tris(alpha-phenylpropionate) with configurational diversity

An improved methodology for microbatch screening in the liquid-solid enantioselective adsorption of racemates by solid chiral selector is presented and illustrated by the evaluation of a series of six cellulose tris(alpha-phenylpropionate) presenting a configurational diversity and cellulose tris (4-methylbenzoate). Analyses were performed on 5 mg scale of chiral selector and 150 microL of supernatant containing a mixture of three test-racemates. Fifteen test-racemates were chosen according to their molecular diversity using a hierarchical clustering approach for seven selected three-dimensional molecular properties. The 15 racemates were sorted in five test mixtures composed of three racemates each according to the following constraints: each triplet of test-racemates can be analyzed without peak overlap on a commercially available chiral stationary phase (CSP). The designed five groups of three racemates may be used for the evaluation of other chiral selectors in view of the preparation of CSPs. This methodology improves the throughput of the evaluation and could be automated.     

Resolution studies on two regioisomeric chiral stationary phases: effects from reversed orientation of an amide group

Two new polymeric chiral stationary phases, incorporating the selectors trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid bis-allylamide, 1 (DEABA) and trans-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene bis-butenoylamide, 2 (DDEBB), respectively, have been evaluated by chromatographic resolution of a series of structurally different racemates. For some groups of compounds, where large separation factors were obtained, more detailed studies were performed by the use of different retention modifiers. As an effect from the reversed orientation of the amide group in the two selectors, the enantiomers of the racemates investigated are separated in opposite order of elution on the two columns.     

Cellulose dimethylphenylcarbamate-bonded carbon-clad zirconia for chiral separation in high performance liquid chromatography.

Porous zirconia particles are very robust material and have received considerable attention as a stationary phase support for HPLC. We prepared cellulose dimethylphenylcarbamate-bonded carbon-clad zirconia (CDMPCCZ) as a chiral stationary phase (CSP) for separation of enantiomers of a set of 14 racemic compounds in normal phase (NP) and reversed-phase (RP) liquid chromatography. Retention and enantioselectivity on CDMPCCZ were compared to those on CDMPC-coated zirconia (CDMPCZ) to see how the change in immobilization method of the chiral selector affects the retention and chiral selectivity. In NPLC, retention was longer and the number of resolved racemates was smaller on CDMPCCZ than on CDMPCZ. However, chiral selectivity factors for some resolved racemates were better on CDMPCCZ than on CDMPCZ. The longer retention on CDMPCCZ is likely due to strong, non-chiral discriminating interactions with the carbon layer on CDMPCZ. In RPLC only two racemates were resolved on CDMPCCZ, but retention times were shorter than, and resolutions were comparable to, those in NPLC, indicating a potential for improving chromatographic performance of the CDMPCCZ column in RPLC with optimized column preparation and separation conditions.     

Synthesis and applications of novel bis(ammonium) chiral ionic liquids derived from isomannide

Carbohydrate-based novel bis(ammonium) chiral ionic liquids have been synthesized by following a straightforward protocol using isomannide as the substrate. Their applications in chiral discrimination and optical resolution of racemates have been established.     

Linear, neutral polysaccharides as chiral selectors in enantioresolution of basic drug racemates by capillary electrophoresis

Summary A comparison of the enantiorecognition ability of linear, neutral polysaccharides was performed on a series of basic drug racemates in acidic running buffer (pH 3.0). Dextrin 20, Dextran 70 and Pullulan were chosen as chiral selectors for their different characteristics. Dextrin 20, high-dextrose equivalent maltodextrin, showed good enantioresolution for a limited number of racemic drugs. In contrast, Dextran 70, a low-equivalent dextrose polysaccharide, exhibited poorer enantioresolution but had wider applicability allowing nine basic racemates to be resolved; in particular, at high concentrations enantioseparation of amphetamine and congeners was achieved in relatively short time. The results obtained appear to support different mechanisms of enantiorecognition for the polysaccharides studied.     

Enantioseparation of 2‐(substituted phenyl)propanoic acids by high‐speed countercurrent chromatography and investigation of the influence of substituents in enantiorecognition

This paper concentrates on the enantioseparation of racemic 2‐(substituted phenyl)propanoic acids by high‐speed countercurrent chromatography with substituted β‐cyclodextrin as the chiral selector, and an investigation of the influence of the substituent on the benzene ring in enantiorecognition between the chiral selector and enantiomer of each racemate is presented. This is an extension research of our previous work on the enantioseparation of 2‐phenyl propanoic acid derivatives, to investigate the relationship between the value of enantioseparation factor and the different substituent on the benzene ring. In total, ten racemic 2‐(substituted phenyl)propanoic acids were investigated, of which four including 2‐(4‐nitrophenyl)propanoic acid, 2‐(4‐methylphenyl)propanoic acid, 2‐(4‐hydroxyphenyl)propanoic acid, and 2‐(4‐chlorophenyl)propanoic acid, were studied by countercurrent chromatography for the first time, and two racemates were successfully enantioseparated. The distribution ratio and enantioseparation factor for all the ten racemates were determined by enantioselective liquid–liquid extraction. The results showed that an electron‐donating group on the benzene ring presents a higher enantiorecognition induced by chiral selector than that of racemates with an electron‐withdrawing group on the benzene ring.     

Enantioseparation of Novel Chiral Tetrahedral Clusters on an Amylose Tris-(3,5-dimethylphenylcarbamate) Chiral Stationary Phase by Normal Phase HPLC

Introduction In recent years, chiral transition metal cluster has at-tracted a great deal of interests due to its potential ap-plication in asymmetric catalytic reaction.1-3 Producing catalysis for asymmetric induction using a rigid chiral framework would not only bring a basically conceptual breakthrough in the asymmetric catalysis, but also en-rich the methodology in the design of new chiral cata-lysts.4 So far, a lot of chiral clusters have been re-ported,5-9 but only a few of them have bee…     

大环抗生素--毛细管电泳手性分离中一种新的手性选择剂

两种类型的大环抗生素对很多外消旋化合物具有显著的手性选择性且手性选择性相互补充:第一种类型含ansamycin (安沙霉素) 特别适合于阳离子外消旋化合物的分离;第二种类型含glycopeptide (糖肽)最适于阴离子的分离.介绍了大环抗生素的结构特征及手性识别机理,讨论了pH值、抗生素类型和浓度、电泳电解质浓度和化学性质、有机改性剂及胶束相等不同实验条件对分离的影响,还概述了几种大环抗生素作为手性选择剂,在毛细管电泳手性分离中的研究近况.     

The impact of the multipolar distribution on chiral discrimination in racemates

This article explores the impact of the multipolar distribution on chiral discrimination in a series of racemic fluids. Discrimination is measured via the difference between the like-like (LL) and the like-unlike (LU) radial distributions in the liquid. We have found previously that the magnitude and orientation of the molecular dipole have a decisive impact on the short-ranged enantiomeric imbalance in racemates. Although quadrupolar and octupolar interactions decrease more rapidly with intermolecular separation, they can be significant at small separations, where enantiomeric imbalances occur. We have carefully selected a number of models in which we isolate the effects of the molecular quadrupole and octupole. We find that discrimination can be greatly enhanced by changes in the quadrupole moments. However, for octupole moments, changes in discrimination are small and some octupoles inhibit discrimination. We identify the quadrupole moment closest to the plane perpendicular to the direction of the molecular dipole as the moment that has the greatest favorable effect on chiral discrimination in racemates. In racemates where this moment is large, we have found differences of up to 40% between the LL and the LU radial distributions.     

Enantiomer separation by enantioselective inclusion complexation–organic solvent nanofiltration

A novel chiral separation process, which utilizes a combination of enantioselective inclusion complexation (EIC) and organic solvent nanofiltration (OSN), was developed. Although EIC is an attractive way to resolve racemates, the difficulties associated with enantiomer recovery and chiral host recycle has limited large-scale applications. EIC coupled with OSN replaces distillation for the recovery of enantiomers from enantioenriched solid complex. A decomplexation solvent is employed to dissociate enantiomers from the complex, and subsequent separation of enantiomers from the chiral host is realized using OSN. The new process was investigated using racemic 1-phenylethanol as the guest and (R,R)-TADDOL as the chiral host. This novel technology expands the application of EIC to the resolution of nonvolatile racemates, and enables large-scale application.     

异噁唑啉及异噁唑烷类化合物在多糖衍生物类柱上的手性拆分

在ＣｈｉｒａｌｃｅｌＯＤ，ＣｈｉｒａｌｃｅｌＯＪ及ＣｈｉｒａｌｐａｋＡＤ等３种多糖类手性固定相上，以各种配比的正己烷－异丙醇为洗脱剂，对７种异口恶唑啉及异口恶唑烷类化合物的对映体进行了手性拆分。考察了这些外消旋物在这些手性柱上的色谱行为。实验结果表明，手性固定相上葡萄糖片段构型的差异和它们高级结构的不同以及手性固定相上的二甲基苯基氨基甲酸酯或对甲基苯甲酸酯等功能团与样品的极性基团之间的相互作用，可能是支配手性拆分的主要原因。方法已用于不对称１，３－偶极环加成反应产物的光学纯度鉴定。     

以L-天冬氨酸为手性选择剂对手性药物的毛细管电泳拆分

以Ｌ－天冬氨酸为手性选择剂,建立了对１０种手性药物旋光异构体的毛细管电泳快速分离方法,优化了分离条件,并对分离机理作了初步探讨。