Derivative Chiral Stationary Phases Research Articles

A new chiral stationary phase based on noscapine: Synthesis, enantioseparation, and docking study.

Noscapine is an isolated compound from the opium poppy, with distinctive chiral structure and chemistry, interacts with other compounds due to having multiple π-acceptors, hydrogen bond acceptors, and ionic sites. Therefore, it has promising applicability for the enantioselective separation of a wide range of polar, acidic, basic, and neutral compounds. A new noscapine derivative chiral stationary phase (ND-CSP) has been synthesized by consecutive N-demethylation, reduction, and N-propargylation of noscapine followed by attachment of a solid epoxy-functionalized silica bed through the 1,3-dipolar Huisgen cycloaddition. The noscapine derivative-based stationary phase provides a considerable surface coverage, which is greater than some commercial CSPs and can validate better enantioresolution performance. The major advantages inherent to this chiral selector are stability, reproducibility after more than 200 tests, and substantial loading capacity. The characterization by Fourier transform infrared (FTIR) spectroscopy and elemental analysis indicated successful functionalization of the silica surface. Chromatographic method conditions like flow rate and mobile phase composition for enantioseparation of various compounds such as warfarin, propranolol, mandelic acid, and a sulfanilamide derivative were optimized. Comparing the experimental results with docking data revealed a clear correlation between the calculated binding energy of ND-CSP and each enantiomer with the resolution of enantiomer peaks.

Synthesis and application of N-3,5-dinitrobenzoyl and C3 symmetric diastereomeric chiral stationary phases.

Three diastereomeric chiral compounds, namely, (R,R)-(+)-2-amino-1,2-diphenylethanol, (1S,2R)-(+)-2-amino-1,2-diphenylethanol, and (1R,2R)-(+)-1,2-diphenylethylenediamine were used as starting materials for preparing three N-3,5-dinitrobenzoyl derivative chiral stationary phases (CSPs) (CSP 1, 2, and 3) and three C3 symmetric CSPs (CSP 4, 5, and 6). The six newly prepared CSPs were applied to the chiral separation of 44 chiral samples by HPLC. Most samples were isolated on CSP 6, with the highest average separation factor among the six newly prepared CSPs.

Chiral separation of four β-blocker enantiomers using high performance liquid chromatography-tandem mass spectrometry based on amylase derivative chiral stationary phases and investigation on their separation mechanism

A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method based on amylose derivatives as chiral stationary phases (CSPs) for the chiral separation of four β-blocker enantiomers (propanolol, metoprolol, arotinolol and carvedilol) was established. The effects of different CSPs, volume fractions of mobile phase modifiers and mobile phase additives, column temperatures and flow rates on the chiral separation of the four β-blocker enantiomers were evaluated. Baseline separation of the four β-blockers enantiomers was obtained on a Chiralpak AD-H chiral column using the mobile phase of n-hexane-ethanol-diethylamine (20:80:0.03, v/v/v) at a flow rate of 0.550 mL/min and a column temperature of 40℃. The resolutions of the enantiomers for propanolol, metoprolol, arotinolol and carvedilol were 1.37, 1.80, 2.09 and 4.70, respectively. The separation mechanism of the four β-blocker enantiomers was investigated by thermodynamic analysis and enantiomeric structure analysis. The chiral separation was all enthalpy controlled, and the cave structure of the chiral stationary phase played an important role on the separation. The method provides reference for further studies of the β-blocker enantiomers.

Preparation of silica microspheres with a broad pore size distribution and their use as the support for a coated cellulose derivative chiral stationary phase.

A templating strategy using crosslinked and functionalized polymeric beads to synthesize silica microspheres with a broad pore size distribution has been developed. The polymer/silica hybrid microspheres were prepared by utilizing the combination of a templating weak cation exchange resin, a structure-directing agent N-trimethoxysilylpropyl-N,N,N-trimethylammonium chloride, and a silica precursor tetraethyl orthosilicate. The silica microspheres were then obtained after calcinating the hybrid microspheres. The as-prepared materials were characterized by scanning electron microscopy, mercury intrusion porosimeter, and thermal gravimetric analysis. The results showed that the starting templating beads were about 5μm in diameter and the formed silica microspheres were less than 3μm with a pore size range of 10-150nm, some pores were even extended to beyond 250nm. It was demonstrated that cellulose tris(3,5-dimethylphenylcarbamate) was readily coated onto the surface of the as-synthesized silica microspheres without any additional surface pretreatment. The coated silica microspheres were uniformly dispersed even with high loading of the chiral stationary phase, which exhibited high resolution chiral separations in high-performance liquid chromatography.

Preparation and chromatographic evaluation of β-cyclodextrin derivative CSPs bearing substituted phenylcarbamate groups for HPLC

ABSTRACTFive β-cyclodextrin (β-CD) derivatives bearing substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 2-, 3-, and 6-positions of glucose unit and another five derivatives containing benzoate at the 2-position and substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 3- and 6-positions were synthesized using the regioselective esterification method. The obtained β-CD derivatives were efficiently immobilized onto the silica gel through the intermolecular polycondensation of a small amount of the triethoxysilyl groups, which were used as the chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). The chiral separation properties of these CSPs were evaluated under the normal-phase HPLC. The effects of solvent polarity and the side chain structures of β-CD derivatives on the chiral recognition ability of the immobilized CSPs were investigated. Among these β-CD derivative CSPs, 2,3,6-tris(3,5-dichlorophenylcarbamate)-β-CD CSP showed a relatively high chiral recognition ability for the studied racemates. The regioselective esterification at the 2-position of glucose unit in the β-CD decreased the chiral recognition ability at the same conditions. For some racemates, the β-CD derivative CSPs showed chiral recognition abilities comparable or better to some chemical bonded β-CD derivative CSPs and 3,5-dichloro- and 3,5-dimethylphenylcarbamates of cellulose and amylose CSPs.

Enantioseparation of Timolol on a Novel β-Cyclodextrin Derivative Chiral Stationary Phase in HPLC.

A novel chiral stationary phase was prepared by bonding a novel β-cyclodextrin derivative on silica gel, and it was used for the separation of timolol in high efficiency liquid phase. In the reverse mode, the factors such as the proportion of chiral additives, flow rate, column temperature, repeatability and stability were investigated. The optimum chromatographic conditions are as follows: column temperature was 25°C, flow rate was 0.6 mL min(-1) and mobile phase was methanol-25 mM KH2PO4 (80/20, v/v). The chiral column has good reproducibility (Rs = 4.49, 4.51 and 4.40, respectively) and a certain degree of stability (Rs = 4.49, 3.01 and 0.72, respectively). This chiral stationary phase presented good chiral recognition performance toward timolol with good resolution (Rs = 4.49).

Preparation and Enantioseparation Characteristics of a Novel β-Cyclodextrin Derivative Chiral Stationary Phase in High-Performance Liquid Chromatography

A novel cyclodextrin (CD) derivative mono(6(A)-N-allylamino-6(A)-deoxy)per-3-chlorine-4-methyl-phenylcarbamoylated-β-CD was synthesized and chemically immobilized onto the surface of γ-mercaptopropyl-functionalized silica gel step by step. The products were all purified and characterized and then got a substance with definitional structure. This chiral stationary phase (CSP) of 3-chlorine-4-methyl-phenylcarbamoylated-β-CD bonded on silica gel exhibited excellent separation capability for several chiral compounds in high-performance liquid chromatography. In the enantiomeric separations of five racemates with a mixture of methanol and aqueous KH2PO4 buffer as the mobile phase, this CSP presented good chiral recognition performance.

多糖誘導体系のキラル充填剤を使用した中圧クロマト用キラルカラムとキラルTLCの開発

多糖誘導体系のキラル充填剤を使用した中圧クロマト用キラルカラムとキラルTLCの開発

Enantioseparation using urea‐ and imide‐bearing chitosan phenylcarbamate derivatives as chiral stationary phases for high‐performance liquid chromatography

Completely deacetylated chitosan was prepared by the treatment of commercial chitosan with 50% aqueous NaOH, and then derivatized into several new chitosan phenylcarbamate derivatives having a urea and an imide moiety at the 2-position of the glucosamine ring by the reaction with isocyanate and phthalic anhydride/isocyanate, respectively. The chitosan derivatives were coated on macroporous silica gel and evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography. The chiral recognition ability of the chitosan derivative was improved using the completely deacetylated chitosan. Among the novel chitosan derivatives, the 3,5-dimethyl-, 3,5-dichloro-, and 3,4-dichlorophenylcarbamate derivatives were found to possess relatively high chiral resolution abilities. The CSPs based on the chitosan phenylcarbamate-urea and -imide derivatives were stable in the presence of chloroform and ethyl acetate as a component of the eluents, and some racemates were better resolved by such eluents. The dichlorophenylcarbamate-imide derivatives showed a high chiral recognition for metal acetylacetonate complexes. The enantiomerization of Al(acac)3 was performed on the chitosan 3,5-dichlorophenylcarbamate-imide derivative CSP and the resulting chromatogram showed a 26% (+)-isomer enrichment.

Capillary electrochromatographic separation of enantiomers under aqueous mobile phases on a covalently bonded cellulose derivative chiral stationary phase

A chemically bonded cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase (CSP) was prepared by a radical polymerization reaction. The prepared CSP was packed into fused-silica capillaries with inner diameter of 75 microm to perform enantiomer separations in CEC. The electrochromatographic behavior of the CSP was investigated. On the prepared CSP, high EOF could be generated under acidic mobile phases, which represented an advantage for the separation of acidic enantiomers. Several neutral, acidic, and basic enantiomers were resolved on the prepared CSP under aqueous mobile phases. The column efficiencies were between 20,000 and 100,000 plates/m, which were much higher than those of HPLC. In addition, it was observed that the separation of some enantiomers benefited from the adoption of THF as mobile phase modifier.

Improved Procedure for Preparation of Covalently Bonded Cellulose Tris‐phenylcarbamate Chiral Stationary Phases

AbstractThe classical method for preparation of covalently boned cellulose derivative chiral stationary phases (CSP) with diisocyanate as spacer was improved. Diisocyanate was firstly allowed to react with 3‐aminopropyltriethoxysilane, and the resulting product was then applied as the spacer reagent to immobilize cellulose derivatives onto silica gel. Influences of the amount and the length of the spacer on the optical resolution ability of the CSP were investigated. Comparing improved procedure to classical diisocyanate method, the cross‐linking between the glucose units of the cellulose derivatives was avoided to the most extent. With the improved procedure, regio‐nonselective ways could be adopted to prepare covalently bonded CSP, which showed an advantage for the rapid preparation.

Enantioseparation and Chiral Recognition Mechanism of Two Novel Organic Phosphonate Derivatives on Chiral Stationary Phases

Direct enantiomeric resolution of two synthesized organic phosphonate derivatives [(2‐Chloro‐phenylamino)‐(2‐hydroxy‐phenyl)‐methyl]‐phosphonic acid diethyl ester (compound 1) and [(2‐Chloro‐phenyl)‐(4‐fluoro‐phenylamino)‐methyl]‐phosphonic acid diethyl ester (compound 2) has been achieved using hexane as the mobile phase with various alcohols as modifiers. The influence of the mobile phase composition and solute structure on the chiral separation was studied. It was found that compound 1 achieved good separation on (S,S)‐Whelk‐O1, cellulose tris(3,5‐dimethylphenylcarbamate) (CDMPC) and cellulose trisphenylcarbamate (CTPC) chiral stationary phases, while compound 2 could be separated on (R,R)‐3,5‐dinitrobenzoyl‐1,2‐diphenylethane‐1,2‐diamine((R,R)‐DNB‐DPEDA) and CDMPC chiral stationary phases. Interestingly, on cellulose derivative chiral stationary phases (CSPs), acidic additive was necessary for enantioseparation of compounds 1 and 2. The chiral recognition mechanism of (S,S)‐Whelk‐O1, (R,R)‐DNB‐DPEDA and cellulose derivative CSPs was explored. On (S,S)‐Whelk‐O1‐CSP, hydrogen‐bonding interactions play an important role in chiral recognition. On (R,R)‐DNB‐DPEDA‐CSP, the dipole‐dipole interactions and π‐π stacking are important to chiral discrimination. On (S,S)‐Whelk‐O1‐CSP and (R,R)‐DNB‐DPEDA‐CSP, a correlation is concluded between elution order and absolute configuration of the analytes. On cellulose CSPs, the inclusion and fitness of solute shape in the chiral cavity significantly contributed to the enantioseparation of solutes. Furthermore, as for the enantioseparation of compound 1, the hydrogen‐bonding interactions play an important role on CTPC, but play a minor role on CDMPC.

Preparation of a positively charged cellulose derivative chiral stationary phase with copolymerization reaction for capillary electrochromatographic separation of enantiomers.

A positively charged chiral stationary phase (CSP) was prepared by chemically immobilizing cellulose 3,5-dimethylphenylcarbamate onto methacryloyldiethylenetriaminopropylated silica (MCDEAPS) via a radical copolymerization reaction. The prepared CSP was evaluated for enantiomer separation in nonaqueous capillary electrochromatography (CEC). Electroosmotic flow (EOF) generated on the prepared CSP could be significantly improved with introduction of positive charges into the CSP, and separation of enantiomers in CEC has been achieved with mobile phases of ethanol and hexane-ethanol, respectively. In addition, we investigated the solvent versatility of the immobilized CSP on enantioseparations in CEC and capillary liquid chromatography (CLC) due to the elimination of dissolution of chiral selector in a number of solvents. Chiral resolution of some enantiomers was improved by adopting tetrahydrofuran (THF) and chloroform as mobile-phase modifiers, respectively.

Enantiomeric resolution of some human aldosterone synthase [CYP 11 B2] inhibitors on derivatized polysaccharide chiral stationary phases

AbstractAldosterone synthase (CYP 11 B2) is a mitochrondrial cytochrome P450 enzyme catalyzing the last steps of aldosterone production in the adrenal cortex. A new pharmacological approach for the treatment of the aldosterone‐induced effects in congestive heart failure and all forms of hyperaldosteronism could be achieved through the use of (CYP 11 B2) inhibitors. The chiral resolution of some of active compounds, namely 1‐(4‐pyridyl(methyl)tetralin (I)), 7‐chloro‐1‐(1‐imidazolyl)tetralin (II), and 5‐hydroxy‐2‐(4‐pyridylmethyl)indane (III), on various polysaccharide derivative chiral stationary phases, namely Chiralcel OD, OJ, OC, and Chiralpak AD and AS, in normal phase mode was achieved. The mobile phase used was hexane/2‐propanol/triethylamine (9 : 1 : 0.1 v/v/v). The flow rate of the mobile phase was 0.8 mL/min and the wavelengths of detection of compounds I, II, and III were set at 288, 271, and 254 nm, respectively. The chromatographic parameters: retention factor (k), selectivity (α), and resolution factor (Rs) were calculated. The chiral recognition mechanisms between these analytes and chiral selectors are discussed.

Capillary electrochromatographic separation of enantiomers on chemically bonded type of cellulose derivative chiral stationary phases with a positively charged spacer.

Positively charged chiral stationary phases (CSPs) were prepared for capillary electrochromatography (CEC) separation of enantiomers by chemically immobilizing cellulose derivatives onto diethylenetriaminopropylated silica (DEAPS) with tolylene-2,4-diisocyanate (TDI) as a spacer reagent. Anodic electroosmotic mobility was observed in both nonaqueous and aqueous mobile phases due to the positively charged amines on the surface of the prepared CSPs. For comparison, the traditionally used 3-aminopropyl silica (APS) was also adopted as the base material instead of DEAPS to prepare CSP. It was observed that the EOF on the DEAPS-based CSP was 18%-60% higher than that on the APS-based CSP under nonaqueous mobile phase conditions. Separation of enantiomers in CEC was performed on the positively charged CSPs with the nonaqueous mobile phases of pure ethanol or mixture of hexane-alcohol and the aqueous phases of acetonitrile-water or 95% ethanol. Fast separation of enantiomers was achieved on the newly prepared CSPs.

Synthesis of covalently bonded cellulose derivative chiral stationary phases with a bifunctional reagent of 3-(triethoxysilyl)propyl isocyanate

A bifunctional reagent of 3-(triethoxysilyl)propyl isocyanate (TEPI) was initially adopted as a spacer reagent to prepare the bonded types of chiral stationary phases (CSPs) with cellulose derivatives. The silica-based CSPs were chemically prepared with non-regioselective and regioselective approaches and their chiral resolving capabilities were evaluated in terms of HPLC resolution of test enantiomers. It was observed that the chiral recognition capabilities of the non-regioselectively prepared CSPs were influenced by the amount of TEPI used. And also, the regioselectively prepared CSP generally showed a slightly higher resolution power than the non-regioselectively prepared CSP, while the non-regioselective procedures were highly advantageous to rapid preparation. In addition, chiral recognition of the prepared CSPs was affected by the properties of the used silica matrices.

Enantiomerization study of some alpha-nitroketones by dynamic high-resolution gas chromatography.

The kinetics of the reversible enantiomer interconversion of 3-nitrobutan-2-one (1), 3-nitropentan-2-one (2), and 2-nitropentan-3-one (3) have been studied by dynamic high-resolution gas chromatography (DHRGC) by using a beta-cyclodextrin derivative chiral stationary phase; the process occurs via enolization of the keto forms. The DHRGC experiments involving the studied nitroketones and the chiral stationary phase show chromatographic profiles with a typical interconversion plateau in the temperature range between 130 and 160 degrees C. Computer simulation of the experimental chromatographic elution profiles was employed for the determination of rate constants and the corresponding enantiomerization barriers (k, DeltaG#(T), DeltaH#, and DeltaS#). The highly negative entropy of activation (DeltaS# values from -19 to -37 cal mol(-1) K(-1)) points to a transition state (TS) with large charge separation. The obtained results for 1-3 show the dramatic effect of an alpha-nitro-substituent on the rate of enolization of simple ketones, when compared with those for 3-chloro-2-butanone and 3-methyl-2-pentanone. To get some information on the separate contributions of the stationary liquid phase and the mobile gas phase on the studied process, some DFT ab initio calculations have been performed for the same compounds.

Enantiomer separation of mandelates and their analogs on cyclodextrin derivative chiral stationary phases by capillary GC.

Enantiomer separation of mandelates and their analogs, which are important intermediates in asymmetric synthetic and pharmaceutical chemistry, was investigated by capillary gas chromatography using different cyclodextrin derivative chiral stationary phases (CD CSPs). The used cyclodextrin derivatives included permethylated beta-CD (PMBCD), permethylated gamma-CD, heptakis(2,6-di-O-butyl-3-O-butyryl)-beta-CD, heptakis(2,6-di-O-pentyl-3-O-acetyl)-beta-CD and heptakis(2,6-di-O-nonyl-3-O-trifluoroacetyl)-beta-CD (DNTBCD), respectively. Among all the CSPs used, PMBCD and DNTBCD exhibited the broadest and best enantioselectivity for all the racemates investigated. Some thermodynamic parameters were evaluated and an enthalpy-entropy compensation effect was observed in enantiomer separation processes of mandelates and their analogs. Based on thermodynamic data and molecular mechanics calculations, the chiral recognition mechanism of mandelate derivatives on CD CSPs is discussed.

Gas chromatographic enantiomer separation on single and mixed cyclodextrin derivative chiral stationary phases

Capillary gas chromatographic enantiomer separation of some polar compounds, including α-phenylethylamine, styrene oxide, pyrethroid insecticides and other carboxylates, was investigated on modified cyclodextrin (CD) chiral stationary phases. The chiral stationary phases studied included permethylated β-CD (PMBCD), heptakis (2,6-di-O-butyl-3-O-butyryl)-β-CD (DBBBCD), heptakis (2,6-di-O-nonyl-3-O-trifluoroacetyl)-β-CD (DNTBCD), the mixture of PMBCD and DBBBCD, and the mixture of PMBCD and DNTBCD. On the mixed chiral stationary phases containing the mixtures of derivatized cyclodextrins, enantiomer separation was improved significantly for some compounds as compared to the single cyclodextrin derivative chiral stationary phases, and synergistic effects were observed for some compounds on the mixed cyclodextrin derivative chiral stationary phases.

Enantiomeric resolution of anti-HIV agents on a cellulose derivative chiral stationary phase. Note II

Anti-HIV enantiomeric 1H, 3H-thiazolo[3, 4-a] benzimidazoles have been stereospecifically analyzed by elution on a column of cellulose tris-(4-methyl-phenylbenzoate)ester adsorbed on macroporous silica (ChiralcelR OJ).