Designed combination of chiral selectors for adjustment of enantioseparation selectivity in capillary electrophoresis.

In this study an attempt has been made to explain the reasons for changing the enantioseparation selectivity in some dual cyclodextrin (CD) systems compared to the use of single chiral selectors in capillary electrophoresis (CE). An explanation for selectivity changes is proposed based on the effect of the chiral selector on the mobility of the analyte. In order to support the proposed mechanism, several dual systems were designed on the basis of the known recognition pattern of enantiomers for individual CDs. In most cases the separation selectivity could be adjusted in a designed way. There was no experimental evidence for simultaneous binding of a given chiral analyte with both chiral selectors or of chiral recognition of an analyte complex with one CD by another CD.     

Elucidation of the mechanism of chiral selectivity in diastereomeric salt formation using organic solvent nanofiltration

Organic solvent nanofiltration (OSN) was used to investigate the mechanism of chiral selectivity in diastereomeric salt formation of alpha-phenylethylamine with D-tartaric acid and di-p-toluoyl-D-tartaric acid as resolving agents; results indicate that for these systems chiral selectivity occurs only upon crystallisation and chiral interactions in solution were negligible.     

Macrocyclic chiral receptors toward enantioselective recognition of naproxen

[structure: see text] A macrocyclic receptor based on a bischromenylurea and an alpha,alpha'-(o,o'-dialkyl)diphenyl-p-xylylenediamine spacer provides a C(2) chiral cavity to associate carboxylates by H-bonds. The extent of the selectivity obtained for the racemic receptor 2 and enantiomerically pure (S)-naproxen is 7.2:1. Steric repulsions close to the cavity are decisive for the chiral selectivity.     

Synthesis and application of a novel single-isomer mono-6-deoxy-6-(3R,4R-dihydroxypyrrolidine)-β-cyclodextrin chloride as a chiral selector in capillary electrophoresis

A novel positively charged single-isomer of β-cyclodextrin, mono-6-deoxy-6-(3R,4R-dihydroxypyrrolidine)-β-CD chloride (dhypy-CDCl), was synthesized and employed as a chiral selector for the first time in capillary electrophoresis (CE) for the enantioseparation of anionic and ampholytic acids. The effects of the running buffer pH, chiral selector concentration, analyte structure and organic modifier on the enantioseparation were studied in detail. The chiral selectivity and resolution for most of the studied analytes decreased as the buffer pH increased in the range of 6.0–9.0. Increasing selector concentration led to decreased effective mobility, increased chiral selectivity and resolution for most of the studied analytes. Moreover, the hydroxyl groups located on the dihydroxypyrrolidine substituent of the dhypy-CDCl could have influence on the chiral separation.     

Modeling and optimization of the chiral selectivity of basic analytes in chiral capillary electrophoresis with negatively charged cyclodextrins using electrochemical detection

A mathematical model concerning the separation selectivity of basic analytes in chiral capillary electrophoresis (CE) modified with negatively charged cyclodextrins (CDs) has been presented to describe the dependence of chiral selectivity on the buffer pH and the chiral selector concentration. The electrophoretic method to determine the parameters of the model has also been developed. The model has been tested with racemic epinephrine and isoproterenol as target analytes and sulfonated beta-CD as chiral selector. The agreements have been found between the calculated and the measured values. Some significant conclusions to optimize chiral CE separation have been derived from the model and proven by the experiments. Electrochemical detection was used to meet the requirement of the low introduced concentration of analytes.     

人红细胞摄取环己二胺合铂(Ⅱ)配合物的手性选择性研究

合成了六种以不同手性的1,2-环己二胺(1,2-dach)作为载体配体的铂(Ⅱ)配合物,用元素分析、红外及分子图形方法对其组成和结构进行了表征.测定了它们跨人红细胞膜的一级反应动力学常数.用膜蛋白巯基滴定、荧光标记、自旋标记ESR谱等方法研究了它们与膜蛋白、膜脂的相互作用;用脂质体模拟了这些配合物的细胞摄入.结果表明:这些配合物主要通过简单扩散进入红细胞,其跨膜速率对环己二胺的手性具有明显的选择性.这种选择性主要来源于配合物与膜脂作用过程中的手性识别。     

手性有机聚合物毛细管电色谱整体柱研究进展

毛细管电色谱具有高分离效率、多种保留机制和高选择性的优点。近年来,利用毛细管电色谱进行对映异构体的手性拆分受到了广泛关注。相对于传统的填充柱和开管柱,整体柱在手性拆分方面具有显著优势。与手性硅基整体柱相似,手性有机聚合物整体柱由于具有大孔,可产生较高的流速而压降较小。该文综述了近十年手性有机聚合物整体柱制备方法的研究进展,将手性有机聚合物整体柱的制备方法分为"原位聚合法"和"手性修饰法"两种,虽然前者制备简单并广泛应用于早期研究,但聚合混合液成分的微小改变即可引起最终聚合物的形态变化,并且大部分带丙烯基的手性选择剂较难从市场购买。因此,手性修饰法因作为手性选择剂基质的整体柱制备且优化只需进行一次的优势而受到普遍关注。亲核取代、杂环开环和点击化学是常用的修饰手段。该文总结了这两种制备方法的应用,同时对未来的研究方向提出参考性意见。     

Fluxionally Chiral DMAP Catalysts: Kinetic Resolution of Axially Chiral Biaryl Compounds

Can organocatalysts that incorporate fluxional groups provide enhanced selectivity in asymmetric transformations? To address this issue, we have designed chiral 4‐dimethylaminopyridine (DMAP) catalysts with fluxional chirality. These catalysts were found to be efficient in promoting the acylative kinetic resolution of secondary alcohols and axially chiral biaryl compounds with selectivity factors of up to 37 and 51, respectively.     

Influence of buffer substances and urea on the beta-cyclodextrin-mediated chiral separation of dipeptides in CE

The influence of buffering substances and urea on the beta-CD-mediated chiral separations of the dipeptides Ala-Phe and Ala-Tyr was studied in the pH range of 2.5-3.8. Only minor effects of the buffer substances on the chiral separation selectivity alpha were observed at a beta-CD concentration of 15 mg/mL. In contrast, the selectivity improved at pH 2.5 but decreased at pH 3.8 upon the addition of 2 M urea. Complexation by beta-CD resulted in a shift of the pK(a) values toward higher values which was more pronounced for the DD-enantiomers of both dipeptides than for the LL-enantiomers. Addition of urea further increased the pK(a) shift. The consequence of this pK(a) shift is an increase of the fraction of the protonated, positively charged form of the peptides which explained the improved chiral separation at pH 2.5 and the reduced selectivity at pH 3.8. A pK(a) shift by the addition of urea was also observed for N-tert-butyloxycarbonyl phenylalanine (BOC-Phe) as a model compound that is strongly complexed by beta-CD. This effect was not stereospecific. Addition of urea resulted in a decrease of the apparent complexation constants between beta-CD and the BOC-Phe enantiomers to the same extent but this did not affect the separation selectivity alpha. For chiral separations that display strong pH dependence such as peptide enantioseparations close to the pK(a) values of the compounds, urea may not solely be regarded as a solubility enhancer for beta-CD but may also influence the separation.     

Enantioseparations in counter-current chromatography and centrifugal partition chromatography

Examples of chiral separations in counter-current chromatography (CCC) and centrifugal partition chromatography (CPC) are not numerous, due to the difficulty of finding chiral selectors highly selective in the liquid phase as well as a combination of solvents that does not destroy the selectivity and retains the capacity to elute chiral isomers of interest. New ideas and new chiral selectors generally come from other separation techniques, as will be highlighted in this review.     

Chiral resolution of flurbiprofen and ketoprofen enantiomers by HPLC on a glycopeptide-type column chiral stationary phase

Vancomycin is an amphoteric, glycopeptide, macrocyclic antibiotic. When attached to 5 microspherical silica gel, vancomycin proved to be an effective chromatographic chiral stationary phase that could be used in the reversed-phase mode. In this study, a bonded vancomycin chiral stationary phase (Chirobiotic Vtrade mark) was investigated for the chiral liquid chromatography analysis of ketoprofen and flurbiprofen. The selectivity factor (alpha) and the chiral resolution factor (RS) of Chirobiotic Vtrade mark were evaluated first as a function of the buffer pH and molarity, and second as a function of organic modifier type and composition of the mobile phase. Four organic modifiers (tetrahydrofuran, 2-propanol, 1,4-dioxane and methanol) have been tested for their selectivity. Optimized conditions using 20% of tetrahydrofuran in ammonium nitrate (100 mM, pH 5) were selected for the enantioseparation of flurbiprofen and ketoprofen from their racemic forms. At pH 5, these acidic compounds are almost negatively charged, while the chiral selector possesses a positive charge allowing it to interact electrostatistically with the analytes. Using these chromatographic conditions, the column stability was excellent over several months of experiments.     

The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights

We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center. Lewis acids capable of adapting square planar geometries, such as Cu(OTf)2, Cu(ClO4)2, and Pd(ClO4)2, were found to be particularly effective at providing high selectivities. Additionally, substitution at the C-5 position of the pyrazolidinone templates has been shown to be critical for optimal selectivity. Reactions of the optimal pyrazolidinone appended with a number of common dienophiles and various dienes demonstrate the utility of this achiral template. Furthermore, catalytic loadings could be lowered to 2.5 mol % with essentially no loss in selectivity. Pi-Pi interactions were evaluated as a means to explain the unusually high selectivity observed at room temperature. Finally, non-C2-symmetric ligands were employed as a test to determine if chiral relay was operative.     

Chiral lariat ethers as membrane carriers for chiral amino acids and their sodium and potassium salts

Four chiral lariat ethers 8–11 containing a (p-methoxyphenoxy) methyl side arm were used for chiral discrimination of amino acids in their zwitterionic form or as potassium and sodium salts in transport across a bulk chloroform membrane with satisfactory selectivity. The carriers that were employed exhibited different transport selectivity relative to the amino acids and their salts under study. The d/l selectivity strongly depends on the amino acids or their salts, and in some cases reverse selectivity has been obtained. The best selectivity was obtained in the case of tyrosine and its potassium salts for all carriers. The transport rates of amino acids and their salts were found to be controlled by factors such as the structure of the carriers and amino acids or their salts. Among these factors, it was also found that the side arm of the lariat ethers plays an important role in the transport process. As a consequence, the main goal of our investigation was to separate the chiral amino acids through liquid membranes.     

Novel Pirkle-type quinine 3,5-dinitrophenylcarbamate chiral stationary phase implementing click chemistry

A new Pirkle-anion exchange hybrid-type chiral stationary phase (CSP-1) has been synthesized by immobilizing 10,11-didehydroquinine 3,5-dinitrophenylcarbamate onto 3-azidopropyl silica gel using click chemistry (1,3-dipolar Huisgen cycloaddition). This chiral selector and CSP contain a strong π-accepting 3,5-dinitrophenyl residue besides the π-basic quinoline group and an ionizable tertiary amino group. In concert with ion pairing it offers π-donor-π-acceptor interactions resulting in an enhancement of the selectivity toward specific π-donating analytes such as aryloxypropionic acids and profens. A representative set of these analytes has been investigated under various chromatographic conditions (polar-organic, reversed- and normal-phase) leading to base-line enantioseparations with selectivity (α) values up to 1.8. Control experiments with related quinine tert-butylcarbamate phase grafted onto the surface either by thioether (Chiralpak QN-AX) or 1,2,3-triazole linker revealed the impact of the additional aromatic moiety in the chiral selector motif.     

Sequence requirements of oligonucleotide chiral selectors for the capillary electrophoresis resolution of low‐affinity DNA binders

We recently reported that a great variety of DNA oligonucleotides (ONs) used as chiral selectors in partial‐filling capillary electrophoresis (CE) exhibited interesting enantioresolution properties toward low‐affinity DNA binders. Herein, the sequence prerequisites of ONs for the CE enantioseparation process were studied. First, the chiral resolution properties of a series of homopolymeric sequences (Poly‐dT) of different lengths (from 5 to 60‐mer) were investigated. It was shown that the size increase‐dependent random coil‐like conformation of Poly‐dT favorably acted on the apparent selectivity and resolution. The base‐unpairing state constituted also an important factor in the chiral resolution ability of ONs as the switch from the single‐stranded to double‐stranded structure was responsible for a significant decrease in the analyte selectivity range. Finally, the chemical diversity enhanced the enantioresolution ability of single‐stranded ONs. The present work could lay the foundation for the design of performant ON chiral selectors for the CE separation of weak DNA binder enantiomers.     

外消旋萘普生酯类在四种纤维素衍生物手性柱上分离及手性 识别机理研究

在纯聚合物型的纤维素三醋酸酯(CTA)、纤维素三苯甲酸酯(CTB)与涂敷型的CTB、纤维素三(4-甲基苯甲酸酯)(CTMB)四种纤维素衍生手性柱上成功地分离了几种外消旋萘普生酯,研究了流动相组成以及溶质的结构对手性分离的影响,探讨了纤维素衍生物手性固定相对外消旋萘普生酯手性识别的机理,得出溶质在固定相手性空腔中体积大小的适应性,尤其是立体结构上的空间适应性是手性识别的关键,不同的固定相这种适应性有所不同,     

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.     

Stereocontrolled palladium-catalysed umpolung allylation of aldehydes with allyl acetates

In the present work the stereocontrolled palladium-catalysed umpolung allylation of aldehydes is described. Allyl acetates are in situ transformed into the corresponding allyl boronates, which directly react with aldehydes. The question of stereocontrol is raised by employing (a) chiral boronating agents (reagent control) and by (b) utilising chiral aldehydes (substrate control). These studies reveal that the approach based on substrate control is superior to the former one with respect to yields and stereoselectivity. Remarkably, this umpolung protocol often yields the 4,5-syn products in high selectivity, which is unprecedented for direct crotylations.     

A highly selective ferrocene-based planar chiral PIP (Fc-PIP) acyl transfer catalyst for the kinetic resolution of alcohols

Novel planar chiral ferrocene nucleophilic catalysts (Fc-PIP) containing both central and planar chiral elements were designed and synthesized for catalytic enantioselective acyl transfer of secondary alcohols. A remarkably efficient catalyst with high selectivity factors (up to S = 1892) was identified. Comparing the combination of central and planar chirality revealed a strong requirement for the "matched" chiral elements, indicating that the stereogenic center of the imidazole rings should present itself on the same face as the ferrocenyl fragment; otherwise, the catalyst is completely inactive. An exclusively stacked transition state that accounts for the high selectivity of the kinetic resolution of secondary alcohols is proposed. Notably, this newly designed catalyst family is suitable for the catalytic kinetic resolution of bulky arylalkyl carbinols, producing esters with extremely high ee (>99%).