Chiral Differentiation Research Articles

Complexation of Fluvastatin Sodium with β-Cyclodextrin: NMR Spectroscopic Study in Solution

1H NMR spectroscopic study of fluvastatin sodium (FLU), β-Cyclodextrin (β-CD) and their mixtures confirmed the formation of FLU/β-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (Ks) was calculated to be 340 M−1. Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the β-CD cavity and there is chiral differentiation by the β-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the β-CD cavity was also established and structure of the complex has been proposed.

Complex formation of D-mannonaphto-18-crown-6-ether and enantiomers of phenylalanine in water studied by different physochemical methods

Complex formation of D-mannonaphto-18-crown-6-ether 1 with D- and L-phenylalanine (Phe) and their derivatives was studied using conduction and titration microcalorimetry in aqueous solution, and solvent–solvent (water–chloroform) extraction. The thermal effects accompanying the complexation process were determined, but the chiral recognition effects were very small. The chiral differentiation of amino acid was observed in the experiments of the extraction from water to chloroform phase containing chiral receptor.

Non-equivalence of d- and l-trehalose in stabilising alkaline phosphatase against freeze-drying and thermal stress. Is chiral recognition involved?

Comparison of the ability of the enantiomeric forms of trehalose to stabilise alkaline phosphatase towards dehydration and heat showed that natural D-trehalose is superior to L-trehalose, although both disaccharides provide some protection for the enzyme. The result of this novel experiment suggests a chiral differentiation between carbohydrate and protein and thus lends support for the water replacement hypothesis of solute-based stabilisation of biomolecules, but the non-crystallinity and the physical form of the L-isomer may also be a key factor.

Comparison of the chiral recognition of prochiral substrates in the acetylation reaction by a novel lipase (CSL) from the yeast, Cryptococcus spp. S-2 with immobilized PPL : Enzyme-catalyzed desymmetrization and asymmetrization of prochiral 2-substituted 1,3-propanediols by CSL and immobilized PPL

In order to elucidate the nature of a novel lipase (CSL), isolated from the yeast Cryptococcus spp. S-2, in chiral recognition by comparison with that of immobilized PPL, the desymmetrization and asymmetrization of prochiral 2-phenyl-1,3-propanediol ( 1a), 2-benzyl-1,3-propanediol ( 1b), 2-methyl-2-phenyl-1,3-propanediol ( 1c), 2-benzyl-2-methyl-1,3-propanediol ( 1d), 2-ethyl-2-phenyl-1,3-propanediol ( 1e), and 2-benzyl-2-ethyl-1,3-propanediol ( 1f) by acetylation was investigated. Acetylation of 1a with excess vinyl acetate by the CSL-enzyme catalyst gave the corresponding monoacetate 2a with high enantioselectivity (80% ee) in 46% yield. Very high levels of desymmetrization were observed in the tertiary systems of 1c– f, giving the corresponding monoacetates 2c– f, respectively, in >97%. In the desymmetrization of diols 1a, 1c, 1d, and 1f, the sense of chiral differentiation of CSL was opposite to that of immobilized porcine pancreatic lipase (PPL).

Chiral Differentiation of DNA Adducts Formed by Enantiomeric Analogues of Antitumor Cisplatin Is Sequence-Dependent

1,2-GG intrastrand cross-links formed in DNA by the enantiomeric complexes [PtCl(2)(R,R-2,3-diaminobutane (DAB))] and [PtCl(2)(S,S-DAB)] were studied by biophysical methods. Molecular modeling revealed that structure of the cross-links formed at the TGGT sequence was affected by repulsion between the 5'-directed methyl group of the DAB ligand and the methyl group of the 5'-thymine of the TGGT fragment. Molecular dynamics simulations of the solvated platinated duplexes and our recent structural data indicated that the adduct of [PtCl(2)(R,R-DAB)] alleviated this repulsion by unwinding the TpG step, whereas the adduct of [PtCl(2)(S,S-DAB)] avoided the unfavorable methyl-methyl interaction by decreasing the kink angle. Electrophoretic retardation measurements on DNA duplexes containing 1,2-GG intrastrand cross-links of Pt(R,R-DAB)(2+) or Pt(S,S-DAB)(2+) at a CGGA site showed that in this sequence both enantiomers distorted the double helix to the identical extent similar to that found previously for the same sequence containing the cross-links of the parent antitumor cis-Pt(NH(3))(2)(2+) (cisplatin). In addition, the adducts showed similar affinities toward the high-mobility-group box 1 proteins. Hence, whereas the structural perturbation induced in DNA by 1,2-GG intrastrand cross-links of cisplatin does not depend largely on the bases flanking the cross-links, the perturbation related to GG cross-linking by bulkier platinum diamine derivatives does.

Application of tetraoxadiaza-crown ether derivatives as chiral selector modifiers in capillary electrophoresis

Two new diaza-crown ether derivatives ( R- 1, RS- 1) have been synthesized from 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane and tested as potential chiral selectors in capillary electrophoresis (CE) for the chiral separation of five amino acid derivatives. The individual use of the selectors did not lead to chiral differentiation. However, they enhanced the enantioselective effect of different cyclodextrins in dual selector systems. In this paper, we report the effect of different substituted diaza-crown ether derivatives on the separation results obtained in dual systems with cyclodextrins.

A permselective biotinylated polydicarbazole film for the fabrication of amperometric enzyme electrodes

We describe herein, the synthesis and electrochemical properties of a chiral biotin derivative substituted by two carbazole groups in organic media (CH 2Cl 2). In the anodic region it has been shown by cyclic voltammetry that the oxidation of the carbazole groups has led to the first example of a cross-linked biotinylated conducting polymer. The resulting modified electrode was applied to the amperometric determination of l- and d-norepinephrines at 0.5 V vs SCE exhibiting a chiral differentiation due to a better permeation of the d-form. Furthermore, the efficient coupling of avidin and biotinylated polyphenol oxidase with the underlying biotinylated polycarbazole film has allowed the formation of an enzyme electrode. Its analytical characteristics were analyzed for the detection of l- and d-norepinephrines at −0.2 V vs SCE. The comparison with its performance to that of a conventional polyphenol oxidase electrode clearly demonstrates that the permselective properties of the polycarbazole film markedly improve the biosensor stereoselectivity.

Ligand and metal-ion effects in metal-ion clusters used for chiral analysis of alpha-hydroxy acids by the kinetic method.

Chiral recognition of alpha-hydroxy acids has been achieved, and mixtures of enantiomers have been quantified in the gas phase, by using the kinetics of competitive unimolecular dissociation of singly-charged transition metal ion-bound trimeric complexes, [M(II)(A)(ref*)(2)-H](+) (M(II)=divalent transition metal ion; A=alpha-hydroxy acid; ref*=chiral reference ligand), to form the dimeric complexes [M(II)(A)(ref*)-H](+) and [M(II)(ref*)(2)-H](+). Chiral selectivity, the ratio of these two fragment ion abundances for the complex containing the analyte in one enantiomeric form expressed relative to that for the fragments of the corresponding complex containing the other enantiomer, ranges from 0.65 to 7.32. Chiral differentiation is highly dependent on the choice of chiral reference compound and central metal ion. The different coordination geometry of complexes resulting from the different d-orbital electronic configurations of these transition metal ions plays a role in chiral discrimination. Of all the transition metal ions examined chiral recognition is lowest for Cu(II), because of large distortion of the coordination complexes, and hence weak metal-ligand interactions and small stereochemical effects. It seems that two independent pi-cation interactions occur when N-acetyl-substituted aromatic amino acids used as the reference ligands and this accounts for improved chiral discrimination. If both metal-ligand and ligand-ligand interactions are optimized, large chiral selectivity is achieved. The sensitive nature of the methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the optical purity, which are intrinsic to the kinetic method, enable mixtures to be analyzed for small enantiomeric excess ( ee) by simply recording the ratios of fragment ion abundances in a tandem mass spectrum.

Analytical Currents: Chiral differentiation of amino acids

Analytical Currents: Chiral differentiation of amino acids

Gas-Phase Chiral Differentiation of Amino Acid Guests in Cyclodextrin Hosts

Gas-Phase Chiral Differentiation of Amino Acid Guests in Cyclodextrin Hosts

Supercritical Fluid Extraction, a Novel Method for Production of Enantiomers.

Extraction of 25 different binary mixtures of racemic acids [2-(4-isobutylphenyl)propionic acid, cis- and trans-chrysanthemic, and -permetric acid] and various chiral bases with supercritical carbon dioxide permitted the conclusion that molecular chiral differentiation in a supercritical fluid is more efficient than in conventional solvents. In the majority of cases, however, complete separation could not be achieved. In five cases, remarkable partial resolutions were realized (30-75% ee) and resolution was possible on a preparative scale. The pair cis-chrysanthemic acid and (S)-(+)-2-(benzylamino)-1-butanol was studied in detail. Pressure, temperature, time, as well as the molar ratio of base and acid had a marked influence on the quantity and quality of the products. Increasing pressure or decreasing temperature resulted in higher ee values. (-)-cis-Chrysanthemic acid in 99% ee was obtained from the raffinate in a single extraction step. Multiple extractions produced the (+)-cis-acid in 90% ee.

Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents

Annellation of a cyclopropyl group to the dibenzosuberane moiety of the prototypical agent MS-073 afforded potent multiple drug resistance modulators. The chiral differentiation observed for the enantiomers of some of these compounds points to a specific interaction with the drug efflux pump, glycoprotein p 170, in contrast to the less specific membrane interaction seen with less potent agents.

Enantiomeric differentiation of a wide range of pharmacologically active substances by capillary electrophoresis using modified β-cyclodextrins

This paper shows the versatility of modified charged and uncharged β-cyclodextrins (CDs) in the direct chiral resolution of β-agonists, β-antagonists, phenylethyamines and alcohol stimulants, and thalidomide and its metabolites. A total of 42 compounds were optically resolved using hydroxypropyl-β-CD and 20 with sodium sulfobutyl ether-β-CD. The degree of enantiomeric separation for most substances is dependent on the modified CD concentration. The separation efficiency reaches a maximum at a particular CD concentration. The separation efficiency reaches a maximum at a particular CD concentration, after which further increases in CD concentration causes a progressive decrease in chiral differentiation. Chiral separation of amphetamine enantiomers indicated that a three-point hydrogen bond interaction between the chiral guest molecule and host CD is not necessary for chiral separation under the conditions used.

Electronic control of enantioselectivity in the palladium-catalyzed asymmetric allylic substitution of trans 4- tbutyl-l-vinylcyclohexyl benzoates

The enantioselectivity in the palladium-catalyzed substitution of allylic benzoates 1 by sodium dimethyinwlonate was influenced by polar and steric effects of the substituents in the phenyl ring of the benzoate. Electron-donating p-substituents afforded effective chiral differentiation (up to 90%ee). Electron-withdrawing substituents, t-butyl-p-substituent, N,N-dialkylamino p-substituents were or o-substituents were detrimental to steric differentiation (down to 22%ee). Di- and tri-methoxy substituted benzoates gave moderate asymmetric inductions (46–70 %ee).

Chiral Differentiation of the Optical Isomers of Racemethorphan and Racemorphan in Urine by Capillary Zone Electrophoresis

A novel capillary zone electrophoretic method based on the use of propanol-modified beta-cyclodextrin buffers has been developed; it unambiguously detects and quantitates the optical isomers of racemethorphan and racemorphan without prior derivatization. Detection limits in urine down to 20 ppb have been obtained. The method uses a solid-phase extraction recovery of analytes followed by ultraviolet detection. Separation conditions include the use of 60mM beta-cyclodextrin and 50mM sodium dodecyl sulfate in a buffer containing 20% 1-propanol.

GC and NMR enantiodiscrimination of 2-methyl substituted aliphatic acids via diastereomeric esterification with (R)-pantolactone

The chiral differentiation of the enantiomers of 2-methylbutanoic acid, 2-methylpentanoic acid and 2-methylhexanoic acid was achieved by diastereomeric derivatization with (R)-( – )-pantolactone. GC separation on achiral DB-1, DB-1701 and DB-WAX capillary columns as well as 1H- and 13C-NMR enantiodiscrimination were obtained, affording good resolution and quantitative evaluation of enantiomer composition. The method applied to 2-methylbutanoic acid present in the aromatic fraction extracted from cultivated strawberry (Fragaria vesca) indicated a high enantiomeric excess of the (S)-isomer.

Chiral differentiation by the P-(+)-hexahelicene-7,7′-dicarboxylic acid disodium salt. Resolution of N-2,4-dinitrophenyl-α-amino-acid esters by high performance liquid chromatography

Derivatives of α- amino-acid esters containing a strong electron acceptor group, were resolved on silica gel coated with a chiral electron donor substance.

Chiral recognition of a prochiral (meso-carbon) centre by Λ(–)436-α-l,l-2,9-diamino-4,7-diazadecanecobaltate

One hundred per cent chiral differentiation of the prochiral carboxyl groups and 65% steric induction is observed in the complexing of Λ(–)436-α-l,l-2,9-diamino-4,7-diazadecanecobaltate with aminomethylmalonate and decarboxylation of the resultant Λ(–)436-α-[l,l-2,9-diamino-4,7-diazadecanecobalt(III)-R-malonate]+ to Λ(–)436-α-[l,l-2,9-diamino-4,7-diazadecanecobalt(III)-S-alanine]2+, respectively.