Resolution of methoxyphenamine and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.

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 ß-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.

Liquid chromatographic ligand-exchange chiral stationary phases based on amino alcohols.

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, ß-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.

Liquid chromatographic resolution of proline and pipecolic acid derivatives on chiral stationary phases based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.

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.

Preparation of Two New Diasteromeric Chiral Stationary Phases Based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid and (R)- or (S)-1-(1-Naphthyl)ethylamine and Chiral Tethering Group Effect on the Chiral Recognition.

Two new diastereomeric chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral tethering group and a Π-basic chiral unit such as (R)-1-(1-naphthyl)ethylamine (CSP 1) or (S)-1-(1-naphthyl)ethylamine (CSP 2) were prepared. The two CSPs were applied to the enantiomeric separation of N-(3,5-dinitrobenzoyl)-1-phenylalkylamines and N-(3,5-dinitrobenzoyl)-α-amino acid derivatives using 20% isopropyl alcohol in hexane as a normal mobile phase. To elucidate the effect of the two chiral units on the chiral recognition, the chiral recognition abilities of the two CSPs were compared with each other and with that of a CSP (CSP 3) based on (R)-1-(1-naphthyl)ethylamine. From the chromatographic chiral recognition results, (R)-1-(1-naphthyl)ethylamine and (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid constituting CSP 1 were concluded to show a cooperative ("matched") effect on the chiral recognition while (S)-1-(1-naphthyl)ethylamine and (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid constituting CSP 2 were concluded to show an uncooperative ("mismatched") effect on the chiral recognition. From these results, it was concluded that (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid can be successfully used as a chiral tethering group for the preparation of new CSPs.

Liquid chromatographic enantioseparations on crown ether-based chiral stationary phases.

Various liquid chromatographic chiral stationary phases (CSPs) have been developed for the resolution of racemic compounds. In particular, CSPs based on chiral crown ethers have been known to be useful in the resolution of racemic compounds containing a primary amino group. In this paper, the development of two types of CSPs based on the chiral crown ethers containing 1,1'-binaphthyl unit(s) or tartaric acid units as chiral barrier(s) and their applications to the resolution of various racemic compounds were reviewed. The structural characteristics of eleven CSPs and their chromatographic behaviors for the resolution of racemic primary amino and non-primary amino compounds were included.

Preparation of a New Chiral Stationary Phase Based on Macrocyclic Amide Chiral Selector for the Liquid Chromatographic Chiral Separations.

A new chiral stationary phase (CSP) based on macrocyclic amide receptor was prepared starting from (1R,2R)-1,2-diphenylethylenediamine. The new CSP was successfully applied to the resolution of various N-(substituted benzoyl)-α-amino amides with reasonably good separation factors and resolutions (α = 1.75 ~ 2.97 and RS = 2.89 ~ 6.82 for 16 analytes). The new CSP was also applied to the resolution of 3-substituted 1,4-benzodiazepin-2-ones and some diuretic chiral drugs including bendroflumethiazide and methylchlothiazide and metolazone. The resolution results for 3-substituted 1,4-benzodiazepin-2-ones and some diuretic chiral drugs were also reasonably good.

Development of HPLC Chiral Stationary Phases Based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid and Their Applications.

Crown ether-based chiral stationary phases (CSPs) have been known to be useful for the resolution of racemic primary amino compounds. In particular, CSPs based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid have been reported to be useful for the resolution of secondary amino compounds as well as primary amino compounds. In this article, the process of developing various CSPs based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to improve the chiral recognition efficiency and/or the stability of the CSPs and their applications to the resolution of various primary and nonprimary amino compounds are reviewed.

Adhesion of Poly(phenylene sulfide) Resin with Polymeric Film of Triazine Thiol on Aluminum Surface Modified by Anodic Oxidation.

Various surface modifications have been applied to improve the adhesion properties of aluminum for the cap plate and sealing quality of electrolyte on Li ion batteries. In this study, we have tried to find the effective condition for the polymerization of triazine thiols (TT) on modified aluminum surfaces by anodic aluminum oxide. Characterization of polymerized films on aluminum was explored by scanning electron microscopy, X-ray photoelectron spectroscopy, and secondary ion mass spectroscopy analysis. Scanning electron microscopy results reveal that meaningful roughness was formed on aluminum surfaces by anodic oxidation. Secondary ion mass spectroscopy analysis results represent that the peel strength was found to depend on film thickness and the composition of the adhesion layer. As a result, Al/PPS (polyphenylene sulfide) resin assemblies developed in this study have superior adhesive property. Therefore, these assemblies might be a viable candidate for a sealing technique for Li ion batteries.

Liquid chromatographic resolution of amino acid esters of acyclovir including racemic valacyclovir on crown ether-based chiral stationary phases.

Valacyclovir, a potential prodrug for the treatment of patients with herpes simplex and herpes zoster, and its analogs were resolved on two chiral stationary phases (CSPs) based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 covalently bonded to silica gel. In order to find out an appropriate mobile phase condition, various mobile phases consisting of various organic modifiers in water containing various acidic modifiers were applied to the resolution of valacyclovir and its analogs. When 30% acetonitrile in water containing any of 0.05 M, 0.10 M, or 0.15 M perchloric acid was used as a mobile phase, valacyclovir and its analogs were resolved quite well on the two CSPs with the separation factors (α) in the range of 2.49 ~ 6.35 and resolutions (RS ) in the range of 2.95 ~ 12.21. Between the two CSPs, the CSP containing residual silanol protecting n-octyl groups on the silica surface was found to be better than the CSP containing residual silanol groups.

Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.

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.

Development of an improved ligand exchange chiral stationary phase based on leucinol for the resolution of proton pump inhibitors.

As an effort to develop improved ligand exchange chiral stationary phases (CSPs) for the resolution of chiral drugs, the residual silanol groups on the silica surface of a CSP based on sodium N-[(S)-1-hydroxymethyl-3-methylbutyl]-N-undecylaminoacetate, a (S)-leucinol derivative, were protected with n-octyl groups. The residual silanol group-protected CSP was applied to the resolution of proton pump inhibitors (PPIs) such as omeprazole, pantoprazole, lansoprazole and rabeprazole. The resolution of PPIs on the residual silanol group-protected CSP was excellent with the separation factors (α) in the range of 4.32-6.42 and the resolution factors (RS) in the range of 6.70-7.15. The improved chiral recognition ability of the residual silanol group-protected CSP was rationalized to be originated from the protection of the non-enantioselective interaction sites on the silica surface and the improved lipophilicity of the stationary phase.

Liquid chromatographic resolution of mexiletine and its analogs on crown ether-based chiral stationary phases.

Mexiletine, an effective class IB antiarrhythmic agent, and its analogs were resolved on three different crown ether-based chiral stationary phases (CSPs), one (CSP 1) of which is based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and the other two (CSP 2 and CSP 3) are based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Mexiletine was resolved with a resolution (R(S)) of greater than 1.00 on CSP 1 and CSP 3 containing residual silanol group-protecting n-octyl groups on the silica surface, but with a resolution (R(S)) of less than 1.00 on CSP 2. The chromatographic behaviors for the resolution of mexiletine analogs containing a substituted phenyl group at the chiral center on the three CSPs were quite dependent on the phenoxy group of analytes. Namely, mexiletine analogs containing 2,6-dimethylphenoxy, 3,4-dimethylphenoxy, 3-methylphenoxy, 4-methylphenoxy, and a simple phenoxy group were resolved very well on the three CSPs even though the chiral recognition efficiencies vary with the CSPs. However, mexiletine analogs containing 2-methylphenoxy group were not resolved at all or only slightly resolved. Among the three CSPs, CSP 3 was found to show the highest chiral recognition efficiencies for the resolution of mexiletine and its analogs, especially in terms of resolution (R(S)).

An interference-free and rapid electrochemical lateral-flow immunoassay for one-step ultrasensitive detection with serum.

Point-of-care testing (POCT) of biomarkers in clinical samples is of great importance for rapid and cost-effective diagnosis. However, it is extremely challenging to develop an electrochemical POCT technique retaining both ultrasensitivity and simplicity. We report an interference-free electrochemical lateral-flow immunoassay that enables one-step ultrasensitive detection with serum. The electrochemical-chemical-chemical (ECC) redox cycling combined with an enzymatic reaction of an enzyme label is used to obtain high signal amplification. The ECC redox cycling involving Ru(NH3)6(3+), enzyme product, and tris(3-carboxyethyl)phosphine (TCEP) depends on pH, because the formal potentials of an enzyme product and TCEP increase with decreasing pH although that of Ru(NH3)6(3+) is pH-independent. With consideration of the pH dependence of ECC redox cycling, a noble combination of enzyme label, substrate, and product [ß-galactosidase, 4-amino-1-naphthyl ß-D-galactopyranoside, and 4-amino-1-naphthol, respectively] is introduced to ensure fast and selective ECC redox cycling of the enzyme product along with a low background level. The selective ECC redox cycling at a low applied potential (0.05 V vs. Ag/AgCl) minimizes the interference effect of electroactive species (L-ascorbic acid, acetaminophen, and uric acid) in serum. A detection limit of 0.1 pg mL(-1) for troponin I is obtained only 11 min after serum dropping without the use of an additional solution. Moreover, the lateral-flow immunoassay is applicable to the analysis of real clinical samples.

Liquid chromatographic resolution of racemic rasagiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.

A liquid chromatographic chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was applied to the resolution of 15 analytes, including racemic rasagiline, a chiral drug for the treatment of Parkinson's disease, and its analogues. The composition of mobile phase was optimized to be ethanol/acetonitrile/acetic acid/triethylamine (80:20:0.2:0.3, v/v/v/v) by evaluating the chromatographic results for the resolution of five selected analytes under various mobile phase conditions. Under the optimized mobile phase conditions, racemic rasagiline was resolved quite well with a separation factor of 1.48 and resolution of 2.71 and its 14 analogues were also resolved reasonably well with separation factors of 1.06-1.54 and resolutions of 0.54-2.11. Among 15 analytes, racemic rasagiline was resolved best except for just one analyte. The analyte structure-enantioselectivity relationship indicated that racemic rasagiline has the most appropriate structural characteristics for resolution on the chiral stationary phase.

Design, synthesis and evaluation of stationary phases for improved achiral supercritical fluid chromatography separations.

A series of novel stationary phases for improved Supercritical Fluid Chromatography (SFC) separation of achiral mixtures is described. Several of these stationary phases show chromatographic performance and generality that is comparable with that of the best commercial stationary phases currently available. The effects of stationary phase structure on chromatographic performance and generality are considered, and suggestions for further improvements in this important field are offered.

Absolute configuration and predominant conformations of a chiral crown ether-based colorimetric sensor: a vibrational circular dichroism spectroscopy and DFT study of chiral recognition.

In the present work, we report a comprehensive vibrational circular dichroism (VCD) spectroscopic study of a chiral crown ether which features an axial chiral 3.3'-diphenyl-1,1'-binaphthyl group as chiral moiety. By comparing the experimental and calculated VCD spectra, we show that the presumably very flexible crown ether preferably adopts only one ring conformation. Conformational flexibility is observed in the 2,4-dinitrophenyl-diazophenol group, which was previously introduced for colorimetric detection of primary amines and amino alcohols (Cho et al., Chirality 2011;23:349-353). The VCD spectra of the host-guest complexes with phenyl glycinol (PG) and phenyl alaninol have been studied as well. Based on the spectra calculated, it is shown that the diastereomeric complexes in general can be differentiated using VCD spectroscopy. Furthermore, the experimental VCD spectra of the complexes of the host molecule with PG support the above finding.

High-performance liquid chromatographic enantioseparation of isoxazoline-fused 2-aminocyclopentanecarboxylic acids on a chiral ligand-exchange stationary phase.

The application of a chiral ligand-exchange column for the direct high-performance liquid chromatographic enantioseparation of unusual ß-amino acids with a sodium N-((R)-2-hydroxy-1-phenylethyl)-N-undecylaminoacetate-Cu(II) complex as chiral selector is reported. The investigated amino acids were isoxazoline-fused 2-aminocyclopentanecarboxylic acid analogs. The chromatographic conditions were varied to achieve optimal separation. The effects of temperature were studied at constant mobile phase compositions in the temperature range 5-45°C, and thermodynamic parameters were calculated from plots of lnk or lnα versus 1/T. Δ(ΔH°) ranged from -2.3 to 2.2 kJ/mol, Δ(ΔS°) from -3.0 to 7.8 J mol(-1) K(-1) and -Δ(ΔG°) from 0.1 to 1.7 kJ/mol, and both enthalpy- and entropy-controlled enantioseparations were observed. The latter was advantageous with regard to the shorter retention and greater selectivity at high temperature. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. The sequence of elution of the enantiomers was determined in all cases.

Effect of the residual silanol group protection on the liquid chromatographic resolution of α-amino acids and proton pump inhibitors on a ligand exchange chiral stationary phase.

A new ligand exchange chiral stationary phase (new CSP) containing residual silanol group-protecting n-octyl groups on the silica surface was prepared by treating a ligand exchange CSP (original CSP) based on sodium N-[(R)-2-hydroxy-1-phenylethyl]-N-undecylaminoacetate bonded to silica gel with excess n-octyltriethoxysilane. The new and original CSPs containing an identical amount of chiral selector were applied to the resolution of α-amino acids and proton pump inhibitors (PPIs) including omeprazole, pantoprazole, lansoprazole, and rabeprazole. The separation factors (α) and resolutions (RS) were greater on the new CSP than on the original CSP except for the resolution of asparagine. The trends of the retention factors (k1) for the resolution of α-amino acids on the new and original CSPs with the variation of the organic modifier content in aqueous mobile phase were opposite to those for the resolution of PPIs. Removal of the nonenantioselective interactions between the residual silanol groups and the analytes and the improved lipophilicity of the new CSP were proposed to be responsible for the improved chiral recognition ability of the new CSP and the different retention behaviors of the enantiomers between the new and original CSPs.

Enantioseparations of primary amino compounds by high-performance liquid chromatography using chiral crown ether-based chiral stationary phase.

Liquid chromatographic resolution of racemic compounds containing a primary amino group has been known to be most successful when chiral crown ether-based chiral stationary phases (CSPs) are used. Among various crown ether-based CSPs, the stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel has been successfully applied in the resolution of various racemic compounds containing primary amino groups. In this chapter, the preparation of the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel and examples for the application to the enantioseparation of racemic compounds including α-amino acids, cyclic amines, amino alcohols, and chiral drugs are described.

Hydroquinone diphosphate as a phosphatase substrate in enzymatic amplification combined with electrochemical-chemical-chemical redox cycling for the detection of E. coli O157:H7.

Signal amplification by enzyme labels in enzyme-linked immunosorbent assays (ELISAs) is not sufficient for detecting a low number of bacterial pathogens. It is useful to employ approaches that involve multiple signal amplification such as enzymatic amplification plus redox cycling. An advantageous combination of an enzyme product [for fast electrochemical-chemical-chemical (ECC) redox cycling that involves the product] and an enzyme substrate (for slow side reactions and ECC redox cycling that involve the substrate) has been developed to obtain a low detection limit for E. coli O157:H7 in an electrochemical ELISA that employs redox cycling. In our search for an alkaline phosphatase substrate/product couple that is better than the most common couple of 4-aminophenyl phosphate (APP)/4-aminophenol (AP), we compared five couples: APP/AP, hydroquinone diphosphate (HQDP)/hydroquinone (HQ), L-ascorbic acid 2-phosphate/L-ascorbic acid, 4-amino-1-naphthyl phosphate/4-amino-1-naphthol, and 1-naphthyl phosphate/1-naphthol. In particular, we examined signal-to-background ratios in ECC redox cycling using Ru(NH(3))(6)(3+) and tris(2-carboxyethyl)phosphine as an oxidant and a reductant, respectively. The ECC redox cycling that involves HQ is faster than the cycling that involves AP, whereas the side reactions and ECC redox cycling that involve HQDP are negligible compared to the APP case. These results seem to be due to the fact that the formal potential of HQ is lower than that of AP and that the formal potential of HQDP is higher than that of APP. Enzymatic amplification plus ECC redox cycling based on a HQDP/HQ couple allows us to detect E. coli O157:H7 in a wide range of concentrations from 10(3) to 10(8) colony-forming units/mL.