Micellar liquid chromatographic green enantioseparation of racemic amino alcohols and determination of elution order.

A micellar liquid chromatographic method was developed for the green enantioseparation of racemic amino alcohols using an aqueous solution of the mixed surfactants as an alternative for organic solvents. In this study, the derivatives of the amino alcohols were synthesized using highly reactive chiral esters of (S)-levofloxacin (Lfx) under microwave conditions, and an aqueous solution of the surfactants (Brij-35 and SDS) was used for the enantioseparation of the synthesized diastereomeric derivatives (DDs) of amino alcohols using reversed-phase HPLC. The activated ester of Lfx was synthesized by reacting with N-hydroxybenzotriazole and characterized using UV, IR, 1 H NMR, high-resolution mass spectrometry, and elemental analysis. The DDs of racemic amino alcohols were separated on a C18 column using micellar LC. Chromatographic conditions were optimized by varying the concentration of the surfactants in aqueous solution and by varying the concentration and pH of the buffer. The green assessment score was calculated for the developed method (score: 82, an excellent green method). In addition, the density functional theory calculations were performed to develop the lowest energy-optimized structures of DDs. The method was validated according to the International Conference of Harmonization guidelines, and the retention factor (k), selectivity factor (α), resolution factor (RS ), limit of detection (0.198 ng mL-1 or 0.291 pM mL-1 ), and limit of quantification (0.594 ng mL-1 or 0.873 pM mL-1 ) were calculated.

Enantioseparation of amino alcohol drugs by nonaqueous capillary electrophoresis with a maltobionic acid-based ionic liquid as the chiral selector.

This study deals with the nonaqueous capillary electrophoretic enantioseparation of twenty-two amino alcohol drugs with a maltobionic acid (MA)-based ionic liquid (tetramethylammonium maltobionic acid, TMA-MA) as the novel chiral selector. In consideration of the poor solubility of MA in organic solvents, we managed to transform MA into ionic liquids (ILs) for the first time. Interestingly, this chiral selector exhibited powerful enantioselectivity towards the model analytes in company with boric acid. Systematical experiments were carried out to investigate the influence of concentration of TMA-MA, boric acid and tris (hydroxymethyl) aminomethane (Tris) as well as applied voltage on the enantioseparation. A great majority of enantiomers (except labetalol) were baseline separated under the optimized conditions and the effect of the molecular structure of amino alcohol drugs on the chiral separation was discussed. In addition, electrophoretic experiments, nuclear magnetic resonance (NMR), mass spectrometry (MS) and molecular modeling with the Gaussian program were employed to demonstrate the mechanism of chiral recognition. Based on the formation of an ionic liquid-boric acid-analyte complex, hydrogen binding was mainly responsible for enantioseparation.

Last ten years (2008-2018) of chiral ligand-exchange chromatography in HPLC: An updated review.

Chiral ligand-exchange chromatography is one of the elective strategies for the direct enantioresolution of small chelating compounds: amino acids, diamines, amino alcohols, diols, small peptides, etc. Unlike other methods, the interaction between chiral selector and analyte enantiomers is mediated by a cation, thus producing diastereomeric ternary complexes. Two main approaches are conventionally applied in chiral ligand-exchange chromatography. The first relies upon chiral stationary phases where the chiral selector is either covalently immobilized or physically adsorbed onto suitable packing materials (coated phases). In the second approach, chiral molecules are added to the eluent, thus generating chiral eluent systems. Among the advantages of chiral ligand-exchange chromatography, the generation of UV/vis-active metal complexes, and the use of commercially available or easy-to-synthesize chiral selectors, in combination to rather inexpensive achiral columns for coated phases and chiral eluents, are noteworthy. Besides amino acids and amino alcohols, other species have proven suitable for chiral ligand-exchange chromatography applications. Recently, the use of either chiral ionic liquids or micellar liquid chromatography systems as well as the successful off-column formation of diastereomeric complexes have expanded the selectivity profiles and application fields. All of these issues are touched in the review, shedding light to the contributions appeared in the last decade.

Chiral high-performance liquid and supercritical fluid chromatographic enantioseparations of limonene-based bicyclic aminoalcohols and aminodiols on polysaccharide-based chiral stationary phases.

Enantioseparation of limonene-based bicyclic 1,3-aminoalcohols and 1,3,5- and 1,3,6-aminodiols was performed by normal-phase high-performance liquid chromatographic and supercritical fluid chromatographic (SFC) methods on polysaccharide-based chiral stationary phases. The effects of the composition of the mobile phase, the column temperature and the structures of the analytes and chiral selectors on retention and selectivity were investigated by normal-phase LC and SFC technique. Thermodynamic parameters derived from selectivity-temperature-dependence studies were found to be dependent on the chromatographic method applied, the nature of the chiral selector and the structural details of the analytes. Enantiorecognition in most cases was enthalpically driven but an unusual temperature behavior was also observed: decreased retention times were accompanied by improved separation factors with increasing temperature, i.e. some entropically driven separations were also observed. The elution sequence was determined in all cases. The separation of the stereoisomers was optimized in both chromatographic modalities.

[Chiral separation of fourteen amino alcohols by nonaqueous capillary electrophoresis].

We developed a new method for chiral separation of fourteen amino alcohols by nonaqueous capillary electrophoresis (NACE) with the D-(+)-gluconic acid δ-lactone-boric acid complex as chiral selector. In order to achieve good enantioseparation, the effects of D-(+)-gluconic acid δ-lactone and boric acid concentrations, triethylamine concentration, as well as capillary temperature were systematically investigated. The optimized conditions were identified as follows: an uncoated fused silica capillary of 50 µm ID with a total length (L(tot)) of 55 cm and an effective length (L(eff)) of 45 cm; 200 mmol·L(-1) D-(+)-gluconic acid δ-lactone, 80 mmol·L(-1) boric acid, and 57.4 mmol·L(-1) triethylamine in methanol; positive pressure injection at 2.9 psi for 2 s; capillary temperature, 25 ± 0.2 ℃; applied voltage, +15 k V; detection wavelength, 214 nm. Under the optimized conditions, a good chiral resolution was achieved in most of the tested drugs. This method provides a foundation for the development and application of new chiral selectors of polyhydroxy compound-boric acid complexes in chiral drugs analysis by NACE.

High-performance liquid chromatographic enantioseparation of amino alcohol analogues possessing 1,2,3,4-tetrahydroisoquinoline skeleton on polysaccharide-based chiral stationary phases.

The stereoisomers of 1,2,3,4-tetrahydroisoquinoline amino alcohol analogues and derivatives thereof were separated in normal-phase mode on chiral stationary phases based on preprepared silica coated with cellulose tris-(3,5-dimethylphenyl carbamate), cellulose tris-(3-chloro-4-methylphenyl carbamate), cellulose tris-(4-methylbenzoate) or cellulose tris-(4-chloro-3-methylphenyl carbamate). On all the investigated chiral columns, the retention and the enantioseparation were influenced by the nature and the concentrations of the mobile phase components and additives, and also the temperature. Experiments were performed in the temperature range 10-50°C. Thermodynamic parameters were calculated from plots of lnα vs 1/T. On these polysaccharide-based chiral columns, both enthalpy-driven separations and entropy-controlled enantioseparations were observed. The latter was advantageous with regard to the shorter retention and greater selectivity at high temperature. The sequence of elution of the stereoisomers was determined in all cases.

Cyclodextrin-mediated enantioseparation of phenylalanine amide derivatives and amino alcohols by capillary electrophoresis-role of complexation constants and complex mobilities.

The separation of the enantiomers of phenylalanine amide and N-methyl derivatives as well as some amino alcohols was studied by CE in acidic BGEs using CDs as chiral selectors. The native CDs displayed only low chiral recognition ability at a concentration of 15 mg/mL in 20 mM sodium phosphate buffer, pH 2.5. In contrast, the analyte enantiomers were separated in the presence of randomly sulfated CDs under reversed polarity of the applied voltage. Sulfated ß-CD proved to be the most universal selector resulting in the enantioseparation of all analytes. Opposite enantiomer migration order depending on the size of the CD cavity was observed for phenylalanine amide and 2-amino-2-phenylethanol. The R-enantiomers migrated first in the presence of sulfated α-CD and γ-CD while the S-enantiomers were detected first in the presence of sulfated ß-CD. The enantioseparations could be rationalized based on analyte complexation by the respective CDs except for 2-amino-2-phenylethanol and sulfated ß-CD where essentially equal complexation constants were derived for the enantiomers. In this case, the migration behavior could be attributed to the mobilities of the enantiomer-CD complexes adding another example to the CE-specific phenomenon of enantioseparations based primarily on complex mobilities.

Amino alcohols from the ascidian Pseudodistoma sp.

Seven new amino alcohol compounds, pseudoaminols A-G (1-7), were isolated from the ascidian Pseudodistoma sp. collected off the coast of Chuja-do, Korea. Structures of these new compounds were determined by analysis of the spectroscopic data and from chemical conversion. The presence of an N-carboxymethyl group in two of the new compounds (6 and 7) is unprecedented among amino alcohols. Several of these compounds exhibited moderate antimicrobial activity and cytotoxicity, as well as weak inhibitory activity toward Na+/K+-ATPase.

Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE.

Divalent dipeptides have been introduced as counter ions in aqueous CZE. The dipeptides form ion pairs with amino alcohols in the BGE and facilitate the separation of amino alcohols. High concentrations of dipeptide caused reversed effective mobility for the analytes. The net charge of the dipeptide can be controlled using a buffer or a strong base, and regulates the interaction between the dipeptide and the amino alcohol. A stronger interaction and higher selectivity of amino alcohols was observed when the dipeptides were used as divalent counter ions, than in monovalent or uncharged form. Association constants for ion pairs between divalent dipeptides and amino alcohols can be used to enhance selectivity for amino alcohols in CZE. No chiral separation of amino alcohols was observed when using the dipeptides as ion-pairing chiral selectors in aqueous BGE, but addition of methanol to the BGE promoted enantioselectivity.

Application of (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as a chiral derivatizing reagent for reversed-phase high-performance liquid chromatographic separation of diastereomers of amino alcohols, non-protein amino acids, and PenA.

Indirect enantioresolution of 15 primary and secondary amino group containing compounds (amino alcohols, non-protein amino acids, PenA) was done using the reagent (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester [(S)-NIFE] by reversed-phase high-performance liquid chromatography. The diastereomeric derivatives were analyzed under reversed-phase conditions using linear gradient. The detection was at 205 nm and sharp peaks were obtained. The reagent used is comparatively economic than the other derivatizing reagents. Method validation was also done.

Comparison of enantioselective HPLC separation of structurally diverse compounds on chiral stationary phases with different teicoplanin coverage and distinct linkage chemistry.

Enantioseparation performance of two teicoplanin-based chiral stationary phases, Chirobiotic T and Chirobiotic T2, with different teicoplanin coverage and distinct linkage chemistry was compared. Three structurally diverse groups of analytes, amino alcohols (beta-blockers), chlorophenoxypropionic acids, and branched-chain amino acids, in various mobile phase compositions/separation modes were examined. The amino alcohols showed better enantioresolution on Chirobiotic T2 in reverse-phase, hydrophilic interaction chromatography, and polar-ionic mode separation systems. The best results with these analytes were obtained in the polar-ionic mobile phase. In contrast, the chlorophenoxypropionic acids and the branched-chain amino acids yielded an improved enantioresolution on the chiral stationary phase with lower amount of teicoplanin in the hydrophilic interaction chromatography system. The comparison of separation of the chlorophenoxypropionic acids enantiomers in the reverse-phase and hydrophilic interaction chromatography environments showed completely opposite results. While better enantioresolution of chlorophenoxypropionic acids was achieved on Chirobiotic T2 in mobile phases with low methanol content, high methanol concentration was needed to reach baseline enantioseparation on Chirobiotic T.

Application of cation-exchange solid-phase extraction for the analysis of amino alcohols from water and human plasma for verification of Chemical Weapons Convention.

The analysis of nitrogen containing amino alcohols, which are the precursors and degradation products of nitrogen mustards and nerve agent VX, constitutes an important aspect for verifying the compliance to the CWC (Chemical Weapons Convention). This work devotes on the development of solid-phase extraction method using silica- and polymer-based SCX (strong cation-exchange) and MCX (mixed-mode strong cation-exchange) cartridges for N,N-dialkylaminoethane-2-ols and alkyl N,N-diethanolamines, from water. The extracted analytes were analyzed by GC-MS (gas chromatography-mass spectrometry) in the full scan and selected ion monitoring modes. The extraction efficiencies of SCX and MCX cartridges were compared, and results revealed that SCX performed better. Extraction parameters, such as loading capacity, extraction solvent, its volume, and washing solvent were optimized. Best recoveries were obtained using 2 mL methanol containing 10% NH(4)OH and limits of detection could be achieved up to 5 x 10(-3) microg mL(-1) in the selected ion monitoring mode and 0.01 microg mL(-1) in full scan mode. The method was successfully employed for the detection and identification of amino alcohol present in water sample sent by Organization for Prohibition of Chemical Weapons (OPCW) in the official proficiency tests. The method was also applied to extract the analytes from human plasma. The SCX cartridge showed good recoveries of amino alcohols from human plasma after protein precipitation.

Preparation of two new liquid chromatographic chiral stationary phases based on diastereomeric chiral crown ethers incorporating two different chiral units and their applications.

Two new liquid chromatographic chiral stationary phases based on diastereomeric chiral crown ethers incorporating two different chiral units such as optically active 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit were prepared. Between the two CSPs, one was much superior to the other especially in the resolution of tocainide and its analogues (for example, in the resolution of tocainide the separation factor, alpha, was 4.26 vs. 1.00 on the two CSPs). From these results, the two chiral units composing the two diastereomeric chiral crown ether moieties of the stationary phases were expected to show "matched" or "mismatched" effect on the chiral recognition according to their stereochemistry. The different chiral recognition abilities of the two CSPs were rationalized by the different three-dimensional structures of the two diastereomeric chiral crown ethers.

Highly Efficient and Robust Enantioselective Liquid-Liquid Extraction of 1,2-Amino Alcohols utilizing VAPOL- and VANOL-based Phosphoric Acid Hosts.

The large-scale production of enantiopure compounds in a cost-effective and environmentally friendly manner remains one of the major challenges of modern-day chemistry. The resolution of racemates through enantioselective liquid-liquid extraction was developed as a suitable solution but has remained largely underused, owing to a lack of highly efficient and robust chiral hosts to mediate the process. This paucity of hosts can in part be attributed to a poor understanding of the underlying principles behind these processes hindering the design of more efficient selectors. A previously untested class of hosts, VAPOL and VANOL derived phosphoric acids, has been studied in depth for the efficient enantioselective liquid-liquid extraction of 1,2-amino alcohols. A systematic investigation of extraction parameters was conducted, revealing many key interactions and DFT calculations illustrate the binding modes for the 1:1 complexes that are involved in chiral recognition. The resulting, now-optimized, procedures are highly robust and easy to implement. They are also easily scalable, as demonstrated by U-tube experiments.

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.

Chiral separation of amino-alcohols using extractant impregnated resins.

The performance of extractant impregnated resin (EIR) technology for chiral separation of amino-alcohols has been investigated. Phenylglycinol was selected as an archetype model enantiomer and azophenolic crown ether was used as a versatile enantioselective extractant. 1-Phenyloctane was selected as a suitable solvent for this application because of its very low solubility in water. The extraction system was first evaluated by liquid-liquid equilibrium experiments. It was shown that crown ether dissolved in 1-phenyloctane has an intrinsic selectivity of 11.5. However, due to very low solubility of phenylglycinol in 1-phenyloctane, the overall capacity of the crown ether solution in 1-phenyloctane is limited. The extractant solution was immobilized in macroporous polypropylene particles. Competitive sorption isotherms were obtained from batch experiments and successfully described with a predictive model based on the complexation constants and partitioning ratios, either obtained from literature or from independent experiments. The equilibrium selectivity of these EIRs approaches the intrinsic selectivity for low phenylglycinol concentrations. The dynamic behaviour and stability of the system were examined in column experiments. Breakthrough profiles as well as the elution curves of the R enantiomer are less sharp than those of the S enantiomer proving that the R enantiomer is strongly retained on the column. Separation of phenylglycinol enantiomers is favoured by using lower feed flow rates. The column was regenerated by water with only atmospheric carbon dioxide dissolved which proved to be sufficient. After several cycles the breakthrough profiles remain unchanged suggesting that these EIRs will be sufficiently stable.

Preparation and evaluation of a chiral stationary phase covalently bound with a chiral pseudo-18-crown-6 ether having a phenolic hydroxy group for enantiomer separation of amino compounds.

In order to develop a chiral stationary phase (CSP), which has even higher separation ability than the corresponding commercially available crown ether based CSP (OA-8000 having a pseudo-18-crown-6 ether with an OMe group as a selector), chemically bonded type CSP having a phenolic OH group on a crown ring was developed. Normal mobile phases with or without acid additive can be used with this OH type CSP in contrast to the conventional OMe type CSP which has a neutral chiral selector. Enantiomers of 25 out of 27 amino compounds, including 20 amino acids, 5 amino alcohols, and 2 lipophilic amines, were efficiently separated on a column with this CSP. Nine amino compounds out of 27 were separated with better separation factors than the corresponding OMe type CSP. It is noteworthy that the chromatography on this CSP exhibited excellent enantiomer-separations for amines and amino alcohols when triethyl amine was used as an additive in the mobile phase. Comparison of enantiomer separation ability on this OH type of CSP and on the OMe type of CSP and correlation between the enantioselectivity in chiral chromatography and that of the corresponding model compounds in solution imply that the chiral separation arose from chiral recognition in host guest interactions.

Signal separation and determination of the enantiomeric purity of primary amines with (-)-myrtenal--a 13C NMR study.

The applicability of (-)-myrtenal as a chiral derivatizing agent in combination with (13)C NMR spectroscopy was investigated. (13)C NMR was found to be a valuable tool for the identification and enantiomer differentiation of primary amines including beta-amino alcohols and vicinal diamines. The enantiomeric excess could be determined via automated deconvolution and integration, and was found to be in good accordance with the expected values even in the cases, when enantiomer differentiation was not possible in (1)H NMR spectra.

Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and target exploration.

Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 µM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 µM and C235 IC50 ≤ 0.28 µM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.

Preparation and evaluation of a chiral stationary phase covalently bound with chiral pseudo-1 8-crown-6 ether having 1-phenyl-1,2-cyclohexanediol as a chiral unit.

A chiral stationary phase (CSP) has been prepared by chemically bonding a chiral pseudo-18-crown-6 type host having a 1-phenyl-1,2-cyclohexanediol unit to 3-aminopropyl silica gel. The chiral column was prepared by the slurry-packing method in a stainless steel HPLC column. Normal mobile phases can be used with this CSP in contrast to conventional dynamic coating type CSPs. Enantiomers of 20 out of 30 amino compounds, including 20 amino acids, 2 amino acid methyl esters, 6 amino alcohols, and 2 lipophilic amines, were efficiently separated on columns with this CSP. It is noteworthy that 15 amino compounds out of 30 were separated with better separation factors and shorter retention times compared to the corresponding CSP having pseudo-18-crown-6 with 1-phenyl-1,2-ethanediol as a chiral unit. In view of the correlation between the enantiomer selectivities observed in chromatography and those obtained in gas phase FABMS-EL methods and solution phase titrations, chiral recognition in the host-guest interaction likely contributes to enantiomer separation.