Enantioseparation of α-amino acids on an 18-crown-6-tetracarboxylic acid-bonded silica by capillary electrochromatography

(−)-(18-Crown-6)-2,3,11,12-tetracarboxylic acid-bonded silica was used as the chiral stationary phase in capillary electrochromatography (CEC) for enantioseparation of some α-amino acids. Separation data in CEC were measured in mobile phases of varying pH, and composition of methanol and buffer, and compared with those in capillary liquid chromatography (CLC). In CEC better enantioseparation was generally obtained in the eluent of lower pH, higher buffer concentration and intermediate MeOH content, usually at the expense of analysis time. CEC showed generally better enantioselectivity and resolutions than CLC for the amino acids investigated.     

Enantioseparation of α-cyclohexylmandelic acid by solvent sublation

Herein we focused on using a novel separation technology, solvent sublation, for the enantioseparation of α-cyclohexylmandelic acid (CHMA). The experiment was carried out in a conventional bubble column using d-iso-butyl tartrate (d-IBTA) and sodium dodecyl sulfate (SDS) as a chiral selector and surfactant, respectively (Fig. 7). Several important parameters influencing the separation performance, such as the type of organic phase, the pH in the aqueous phase, and the concentrations of CHMA, d-IBTA, and SDS were investigated. Under the optimal operating conditions, the enantiomeric excess and separation factor were 54.85% and 4.5, respectively. The yields of d-enantiomer and l-enantiomer were 82.20% and 38.94%, respectively. Finally, the thermodynamic properties of the separation were investigated, which indicated an enthalpy-controlled process. This technique is an efficient chiral separation method, with many advantages, such as low amounts of organic solvent and chiral selector required and easier realization of the multi-stage operation.     

Chiral separation of β-adrenergic blockers on CelluCoat column by HPLC

The chiral separation of 10 β-adrenergic blockers (acebutalol, alprenolol, bufuralol, bisoprolol, celiprolol, carazolol, indenolol, metoprolol, oxprenolol and propranolol) was achieved on CelluCoat column (250 mm × 4.6 mm, 5 μm particle size). The mobile phases used were (90:10:0.2, v/v/v) and (95:5:0.2, v/v/v) combinations of n-heptane-ethanol-diethylamine, respectively. The flow rates were 0.5, 1.0 and 2.0 mL min⁻¹ with detection at 225 nm. The capacity (k), selectivity (α) and resolution (R_s) factors were 0.44-12.91, 1.12-2.19 and 1.00-9.50, respectively. The proposed supra-molecular models indicated that the chiral resolution were governed by π-π interactions, hydrogen bondings and steric effect.     

Diastereoselective aldol reaction of an α-alkoxycarbonylamino aldehyde with a silyl enol ether

The aldol reaction of optically active α-alkoxycarbonylamino aldehydes with a silyl enol ether in the presence of a Lewis acid afforded γ-amino-β-hydroxyketones diastereoselectively. The effect of the α-amide proton on the diastereoselectivity is discussed.     

LC Enantioseparation of Tryptophan Analogs on α-Cyclodextrin Stationary Phase

For the direct separation of enantiomers of tryptophan analogs, a native α-cyclodextrin-based Cyclobond III chiral stationary phase was examined. The separation conditions were optimized by variation of the different chromatographic parameters, and data are reported as retention factors, separation factors and resolutions. The nature and concentration of the buffers as mobile phase additivies exerted only slight effects on the retention and resolution. In all cases, the erythro isomers could be separated significantly better than the threo ones. With increasing hydrophobicity of the analytes, the retention time increased, but no clear trend could be observed between the resolution and the hydrophobicity. The sequence of elution of the enantiomers was in most cases determined by spiking the racemic samples with enantiorich analytes.     

Complex formation of crown ethers with α-amino acids: Estimation by NMR spectroscopy

Complex formation of 18-crown-6 and dibenzo crowns with glycine, leucine, and norleucine was studied by NMR spectroscopy. The efficiency of non-valence interactions with participation of different active centers of the host and guest molecules is determined by solvation effects, mutual arrangement of benzene rings in dibenzo crowns, and the presence of bulky aliphatic substituents in the α-amino acid. The complexation of dibenzo crowns with α-amino acids in acid medium involves a system of different non-valence interactions, the most efficient of which are NH ₃ ⁺ ... O hydrogen bond between the ammonium group in the guest molecule and ether oxygen atoms in the host molecule and dipole-dipole interaction between the guest ammonium group and host benzene ring (NH ₃ ⁺ ... Ar). The efficiency of NH ₃ ⁺ ... O hydrogen bonding decreases in going from 18-crown-6 to dibenzo crowns due to distortion of symmetry of the macroring cavity and violation of geometric complementarity of some ether oxygen atoms. The integral efficiency of non-valence interactions in the system dibenzo crown-α-amino acid was estimated on a quantitative level by ¹H NMR relaxation technique.     

Enantioselective separation of thalidomide on an immobilized α1-acid glycoprotein chiral stationary phaseglycoprotein chiral stationary phase

Summary An easy and rapid enantioselective separation for assay of racemic thalidomide on an immobilized α₁-acid glycoprotein chiral stationary phase (GPA CSP) is described. The effects of tetrahydrofuran (THF) as organic modifier, buffer concentration to control the ionic strenth, and mobile phase pH were studied. These variations have consequences in terms of chromatographic retention (k), resolution (R _s), selectivity (α), and peak asymmetry (USP tailing factor). The main condition affecting chromatographic retention was mobile phase pH. At pH 4.5, no separation of thalidomide enantiomers was achieved whereas at pH 7.9 chiral separation was optimum. Peak tailing was directly related to changes in pH and to addition of THF as mobile phase modifier. Results also indicated that the resolution factor is THF concentration-dependent, and that the separation factor (α) is the best parameter for evaluating enantioselectivity. The best mobile phase was pH 7.0, 30 mM ammonium acetate containing 0.3% THF. Under these conditions validation including linearity, recovery, and precision was performed. The suitability of this method has been successfully proved in a limited in-vivo study after intravenous administration of thalidomide to a New Zealand male rabbit.     

Metallation–substitution of an α-oxygenated chiral nitrile

Deprotonation of a chiral alpha-oxygenated nitrile with the base 2,2,6,6-tetramethylpiperidylmagnesium chloride, TMPMgCl, gives rise to a chiral magnesiated nitrile, and this anion has sufficient configurational stability at low temperature to allow the formation of highly enantiomerically enriched substituted nitrile products after electrophilic quench.     

Separation of racemiccloso-3,3-(η3,2-norbornadienyl)rhodacarboranes into enantiomers by HPLC on chiral stationary phasesinto enantiomers by HPLC on chiral stationary phases

Racemiccloso-rhodacarboranes,vis. closo-(η^3,2-C₇H₃-2-CR ₂ ¹ )-1-R²-2-R³-3,1,2-RhC₂B₉H₉ (R¹=R²=R³=H; R¹=H, R²=R³=Me; R¹=R²=R³=Me) and (closo-2,2-(η^3,2-C₇H₇-2-CH₂)-2,1,7-RhC₂B₉H₁₁), were successfully separated into enantiomers by high-performance liquid chromatography (HPLC). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 759–761, April, 2000.     

Two highly stable and selective solid phase microextraction fibers coated with crown ether functionalized ionic liquids by different sol–gel reaction approaches

In this work, two novel crown ether functionalized ionic liquid (FIL)-based solid phase microextraction (SPME) fibers were prepared by sol–gel technology using the synthesized 1-(trimethoxysily)propyl 3-(6′-oxo-benzo-15-crown-5 hexyl) imidazolium bis(trifluoromethanesulphonyl)imide ([TMSP(Benzo15C5)HIM][N(SO₂CF₃)₂]) and 1-allyl-3-(6′-oxo-benzo-15-crown-5 hexyl) imidazolium bis(trifluoromethanesulphonyl)imide ([A(Benzo15C5)HIM][N(SO₂CF₃)₂]) as selective stationary phases. Owing to the introduction of trimethoxysilypropyl to the imidazole cation, the [TMSP(Benzo15C5)HIM][N(SO₂CF₃)₂] could be chemically bonded to the formed sol–gel silica substrate through the hydrolysis and polycondensation reaction. Similarly, the [A(Benzo15C5)HIM][N(SO₂CF₃)₂] was able to participate in the formation of the organic–inorganic copolymer coatings through the free radical crosslinking reaction. These two fibers were determined to have “bubble-like” surface characteristics analogous to a previously prepared [A(Benzo15C5)HIM][PF₆]-based fiber. Their thermal stabilities were much higher than that of the [A(Benzo15C5)HIM][PF₆]-based coating. They were capable of withstanding temperatures as high as 400 °C without evident loss of the crown ether FILs. They also had strong solvent, acid and alkali resistance, good coating preparation reproducibility and high selectivity for medium polar to polar compounds. The high selectivity of these two fibers could be attributed to the strong ion-dipole, hydrogen bonding and π–π interactions provided by the synergetic effect of ILs and benzo-15-crown-5 functionalities. Moreover, the selectivity of these two fibers was rather different although the structures of these two crown ether FILs were very similar. This is maybe because the relative contents of the crown ether FILs chemically bonded to the organic–inorganic copolymer coatings were quite different when prepared by different sol–gel reaction approaches.     

Fabrication and evaluation of chiral monolithic column modified by β-cyclodextrin derivatives

Based on combination of chiral recognition ability of β-cyclodextrin (β-CD) derivatives and flexibility of monolithic material, a series of chiral stationary phases (CSPs) were prepared by the immobilization of β-CD and three of its derivatives to the epoxy-activated poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith under mild condition. Immobilization condition for the connection reaction by different functional groups and bonding ways was studied to obtain good enantiomer selectivity. Prepared CSPs were evaluated by separating racemic mixtures of eight amino acids and two chiral drugs with capillary electrochromatography (CEC).     

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…     

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

Amylose tris(3,5-dimethylphenylcarbamate) (ADMPC) coated on a kind of small particle silica gel was prepared. On this ADMPC chiral stationary phase (CSP), the direct enantiomeric separation of six novel chiral transition metal tetrahedral clusters has firstly been achieved using n-hexane as the mobile phase containing various alcohols as modifiers. The effect of mobile phase modifiers and the structural variation of the solutes on their retention factors (k‘) and resolutions (Rs) were investigated. The result suggests that not only the structure and concentration of alcohol in mobile phase, but also the structural differences in racemates can have a pronounced effect on enantiomeric separation. ADMPC-CSP is a suitable CSP for the optical resolution of chiral tetrahedral cluster by HPLC.     

Enantioseparation of five racemic N-alkyl drugs by reverse phase HPLC using sulfobutylether-β-cyclodextrin as a chiral mobile phase additive

Analytical enantioseparations of five N-alkyl drugs, fluoxetine hydrochloride, labetalol, venlafaxine hydrochloride, trans-paroxol, and atropine sulfate, were investigated by reverse phase high-performance liquid chromatography with sulfobutylether-β-cyclodextrin as chiral mobile phase additive. Effects of various factors such as composition of mobile phase, concentration of cyclodextrins, and column temperature on retention and enantioselectivity were studied. Apparent formation constant between methanol, acetonitrile, and sulfobutylether-β-cyclodextrin were determined to be 2.90 × 10⁻³ and 1.00 × 10⁻⁴ L mmol⁻¹ under 25°C using UV-spectrophotometry. Van't Hoff plots were used to investigate thermodynamic parameters for enantiomers–stationary phase interaction and formation of inclusion complex. Two retention models were employed individually for evaluation of inclusion complexation between five racemates and sulfobutylether-β-cyclodextrin. The second model with complex adsorption was more accord with the retention behavior of fluoxetine hydrochloride, labetalol, and venlafaxine hydrochloride enantiomers, while the first model was more consistent with the retention behaviors of trans-paroxol and atropine sulfate. In the selected mobile phase, stoichiometric ratio for both of inclusion complex was found to be 1:1.     

Epoxidation of styrene catalyzed by manganese (Ⅲ) porphyrins supported on chloromethylated polystyrene resin bearing crown ether groups

Metalloporphyrins and crown ether groups were simultaneously supported on chloromethylated polystyrene resin to produce a series of polymer-supported catalysts. The synthesis of these catalysts has been studied. The influence of pH, concentrations of NaOCl and phase transfer catalysts on the epoxidation of styrene catalyzed by these catalysts has also been investigated. The experimental results show that manganese(Ⅲ) porphyrin bound to chloromethylated polystyrene which bears crown ether groups is effective catalysts for the epoxidation of styrene by sodium hypochlorite. The introduction of crown ether groups increases the catalytic efficiency of supported metalloporphyrins. The kinetics of epoxidation catalyzed by supported manganese(Ⅲ) porphyrins obeys Michaelis-Menten equation-the characteristic of enzyme-driven reaction.     

Desymmetrizing asymmetric ring expansion of cyclohexanones with α-diazoacetates catalyzed by chiral aluminum Lewis acid

Chiral aluminum Lewis acid catalyst composed of Me(3)Al and 3,3'-bis(trimethylsilyl)-BINOL in a 2:1 ratio was found to promote novel catalytic asymmetric ring expansion of cyclohexanone with α-substituted α-diazoacetates to give seven-membered rings with an all-carbon quaternary center. Application of this strategy to 4-substituted cyclohexanones opened up a novel way for the catalytic desymmetrizing asymmetric construction of cycloheptanones bearing remote α,δ-chiral centers.     

Asymmetric Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by chiral tertiary amine thiourea

A highly diastereoselective and enantioselective Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by bifunctional tertiary amine thioureas has been developed. Various chiral succinimide derivatives bearing adjacent quaternary and tertiary stereocenters were prepared in excellent yields (up to 98%), diastereoselectivities (up to 99:1), and enantioselectivities (up to 98% ee). The synthetic utility of chiral succinimide derivatives is also demonstrated in the preparation of h5-HT(1d) receptor agonist motifs.     

Asymmetric epoxidation of α-substituted acroleins catalyzed by diphenylprolinol silyl ether

Asymmetric epoxidation of α-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether to afford α-substituted-β,β-unsubstituted-α,β-epoxy aldehyde with excellent enantioselectivity and the generation of a chiral quaternary carbon center. The method was applied to a short synthesis of (R)-methyl palmoxirate.