Design,Preparation and Application of a New π‐Basic Chiral Stationary Phase for the Liquid Chromatographic Separation of Enantiomers

A new reciprocal π‐basic chiral stationary phase (CSP) was designed based on the reciprocity conception of chiral recognition and prepared starting from (S)‐leucine. The CSP thus prepared was applied in resolving various π‐acidic N‐(3,5‐dinitrobenzoyl)‐α‐amino amides and esters and found to be very effective. Especially, N‐(3,5‐dinitrobenzoyl)‐α‐amino N,N‐dialkyl amides were resolved very well on the new reciprocal CSP. From the chromatographic resolution results and based on the reciprocity conception of chiral recognition with the aid of Corey/Pauling/Koltan (CPK) molecular model studies, a chiral recognition mechanism which utilizes π‐π interaction and simultaneously two hydrogen bonding interactions between the CSP and the analyte has been proposed. The CSP prepared in this study was also successful in resolving 3,5‐dinitrophenylcarbamate derivatives of 2‐hydroxycarboxylic acid esters.     

Study of chiral recognition mechanism of O,O-diethyl (p-methylbenzenesulfonamindo)-aryl(alkyl)-methylphosphonates by HPLC with a series of CSPs

Five chiral stationary phases (CSPs) were used to separate the enantiomers of a series of O,O-diethyl (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. A chiral recognition mechanism was presented to explain the resolution of these compounds. Results show that CSP with strong π-acceptor 3,5-dinitrobenzoyl group and high steric hindrance has the best resolution ability in chiral separation of O,O-diethyi (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. When a CSP has just a strong π-acceptor 3,5-dinitrobenzoyl or high steric hindrance it does not have good chiral resolution ability. The chiral recognition is more difficult when the CSP has more than one asymmetric center.     

Chiral stationary phase design: A study in optimization

A π-basic, brush-type chiral stationary phase (CSP) derived from (S)-N-(1-naphthyl)leucine undecenyl ester has been shown to effectively separate the enantiomers of a broad array of π-acidic analytes. Armed with a mechanistic hypothesis as to how this CSP differentiates between the enantiomers of π-acidic derivatives of α-amino acids, the structure of this CSP was modified in a series of steps, each intended to enhance the enantioselectivity of the CSP. Specifically, brush-type CSPs were prepared from N-(5-naphthyl)leucine di-n-propyl amide and from N-(5-acenaphthyl)leucine di-n-propyl amide. The latter selector was also incorporated into a polysiloxane, then coated and bonded to silica. The rationale for each of the structural changes, and its effect on the enantioselectivity of the resulting CSP is described.     

Resolution of N-acyl-1-naphthylalkylamide on amide and sulfonamide-derived π-acidic chiral stationary phases

Two π-acidic chiral stationary phases (CSP 3, CSP 4) were prepared by connecting the N-3,5-dinitrobenzamide derivative or 2,4-dinitrobenzenesulfonamide derivative of (S)-leucinol to silica gel through the carbamate linkage. The CSPs were applied in resolving seven racemic N-acyl-1-naphthylaminoalkanes by chiral HPLC, and the chromatographic resolution results were compared. From the comparison of the resolution results of the two CSPs, the role of amide and sulfonamide group in each chiral selector of CSP 3 and CSP 4 and an iso-butyl and phenyl group on the chiral center of each CSP 2 and CSP 3 were explained.     

The Resolution of Enantiomeric Ibuprofen on Chiral Stationary Phases Containing N-Arylcarbamoyl Derivatives of Phenylglycine

A series of fourteen anilide derivatives of ibuprofen were resolved on six chiral stationary phases (CSPs) derived from N-arylcarbamoyl derivatives of (S)-phenylglycine. Excellent chiral resolutions were achieved on these CSPs. The ionic-type CSPs showed better chiral recognition abilities than the corresponding covalent-type CSPs, and the CSP bearing two chiral centers has better performance than the CSPs bearing only one chiral center. The highest separation factor was achieved using the ionic-type CSP bearing two chiral centers for the resolution of the 3,5-dinitroanilide derivative of ibuprofen. This result is better than those reported in literature for the resolution of ibuprofen on the CSPs derived from amino acids, According to the chromatographic behaviors, the hydrogen bonding interaction, the π-π interactions provided by the phenyl groups in CSPs bearing one chiral center, and the phenylethylcarbamoyl moiety in CSPs bearing two chiral centers dominate the chiral recognition.     

Liquid chromatographic resolution of 2-hydroxycarboxylic acids on a new chiral stationary phase derived from (S)-leucine

Enantiomers of racemic 2-hydroxycarboxylic acids have been resolved as their O-ethoxycarbonyl pi-basic anilide derivatives on a new chiral stationary phase (CSP) derived from N-(3,5-dinitrobenzoyl)leucine N-phenyl N-alkylamide and the resolution results have been compared with those on various commercial pi-acidic CSPs. The resolution results demonstrate that the new CSP derived from N-(3,5-dinitrobenzoyl)leucine N-phenyl N-alkylamide is most effective among the five CSPs tested for the resolution of 2-hydroxycarboxylic acid derivatives. In order to elucidate the chiral recognition mechanism exerted by the new CSP, the resolution of slightly differently modified derivatives of 2-hydroxycarboxylic acids on the new CSP has been investigated. Based on the resolution results, a chiral recognition mechanism utilizing three simultaneous interactions such as the face to face pi-pi interaction and the two hydrogen bonding interactions between the CSP and the more retained enantiomer of the analyte has been proposed.     

Mechanistic Evaluation of the Resolution of Racemic N-Acyl-1-arylaminoalkanes on (-Acidic Chiral Stationary Phases

Evaluation of a chiral separation mechanism of a racemic compound is very important to the development of more efficient CSP for a better resolution of the racemic compound. Racemic N-acyl-1-arylaminoalkanes were resolved on the three different Pirkle type (-acidic chiral stationary phases(CSPs), phenylglycine DNB CSP(CSP 1),norephedrine DNB CSP(CSP 2), and phenylglycinol DNB CSP(CSP 3).     

Direct Chromatographic Resolution of P-Chiral Organophosphorus Compounds at Analytical and Preparative Levels

Abstract

High-performance liquid chromatography utilizing chiral stationary phases (CSPs) is well established as a very simple and efficient method for obtaining discrete amounts of optically active compounds with high e.e., as well as for determining their enantiomeric composition We wish to demonstrate in the present work that a totally synthetic brush-type π-acidic CSP based on a bis(N,N′-3,5-dinitrobenzoyl) derivative of (R,R)- or (S,S)-trans-1,2-diaminocyclohexane as selector can be used successfully to resolve variety of chiral organophosphorus compounds containing stereogenic centers at phosphorus     

Evaluation and Comparison of a 3,5‐Dimethylphenyl Isocyanate Teicoplanin with Phenyl Isocyanate Teicoplanin Chiral Stationary Phase Using RP‐HPLC

HPLC enantiomeric separations of 8 α‐amino acids were achieved using two self‐made chiral stationary phases (CSP)–phenyl isocyanate teicoplanin (Phe‐TE) and 3,5‐dimethylphenyl isocyanate teicoplanin (DMP‐TE), using reversed phase mobile phases. The Phe‐TE or the DMP‐TE CSP was prepared from the TE using derivative agents, phenyl isocyanate or 3,5‐dimethylphenyl isocyanate, respectively. The chromatographic results were given as the retention, selectivity, resolution factor and the enantioselective free energy difference corresponding to the separation of the two enantiomers. The effect of pH, organic modifier type and amount were discussed, and the stereoselectivities for two TE‐based CSPs were compared. The chiral selectivity factor for six α‐amino acids on DMP‐TE is somewhat bigger than that on Phe‐TE CSP under reversed phase (RP) mode. Comparison of the enantiomeric separations using self‐made Phe‐TE and DMP‐TE was conducted to gain a better understanding of the chiral recognition mechanism of the macrocyclic glycopeptide CSP.     

Preparation and functionalization of reactive monodisperse macroporous poly(chloromethylstyrene-co-styrene-co-divinylbenzene) beads by a staged templated suspension polymerization

Reactive monodisperse porous poly(chloromethylstyrene-co-styrene-co-divinylbenzene) beads have been prepared by a staged templated suspension polymerization method with different concentrations of linear polystyrene porogen and chloromethylstyrene in the polymerization mixture. The presence of a small amount of linear polystyrene in the polymerization mixture leads to a dramatic increase in both the pore size and the pore volume of the resulting beads. In contrast, addition of chloromethylstyrene leads to lower surface areas and smoother surfaces due to the reduced compatibility between the polystyrene porogen and the newly formed crosslinked chains. The modification of chloromethylstyrene beads by Gabriel synthesis to obtain aminated beads has also been studied. The final number of primary amino groups is related to the starting concentration of functional benzyl chloride moieties rather than to the porous properties. Both π-basic and π-acidic type chiral selectors, (R)-1-(1-naphthyl)-ethylamine and (R)-N-(3,5-dinitrobenzoyl)phenylglycine, respectively, have been attached to the amino functionalized beads, and the resulting chiral beads have been used in the model HPLC separations of enantiomers. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2631–2643 1997     

(1S,2R)-N-(3,5-Dinitrobenzoyl) Norephedrine Bonded to Silica Gel as a Chiral Stationary Phase for the Liquid Chromatographic Separation of Enantiomers

Abstract

A Chiral Stationary Phase (CSP 3) was prepared by connecting (1S,2R)-N-(3,5-dinitrobenzoyl) norephedrine to a silica support through an ester linkage. CSP 3 was found to show some differences from CSP 1, derived from N-(3,5-dinitrobenzoyl) phenylglycine, in the resolution of N-acyl-1-aryl-1-aminoalkanes. For example, CSP 3 was found to show greater chiral recognition for conformationally rigid analytes than does CSP 1. On the other hand, CSP 1 was found to resolve flexible analytes better than CSP 3. To explain the chiral recognition behavior on CSP 3, the role of the conformational flexibility of CSP 3 in chiral recognition is proposed.     

Effect of the Amide Connecting Tether Type of Pirkle-Concept Chiral Stationary Phases Derived from (S)-N-(3,5-Dinitrobenzoyl)Leucine on Enantiomeric Separations

ABSTRACT

Liquid chromatographic comparisons are made between a secondary amide linked chiral stationary phase (CSP 1) and a tertiary amide double-tethered CSP (CSP 2) derived from (S)-N-3,5-[dinitrobenzoyl(DNB)]leucine. For the enantioseparation of the anilide derivatives of N-9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (CBZ) and t-butoxycarbonyl (BOC) protected α-amino acids, CSP 2 shows performance superior to that of CSP 1. It is considered that the amide hydrogen of the connecting tether of CSP 1 serves as a nonproductive adsorption site, while the enhanced basicity of the carbonyl oxygen of the tertiary amide tethered CSP 2 is responsible for the increased enantioselectivity of these analytes. For the same reason, it is observed that CSP 2 provides better separation of the enantiomers of N-CBZ α-amino acids as ethyl ester, n-butylamide and diethylamide derivatives than CSP 1.     

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 (R_S) 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.     

非均匀取代淀粉衍生物手性固定相的制备及其手性识别能力

通过区域选择性方法制备了两种新型淀粉衍生物,分别为淀粉2-苯甲酸酯-3-(4-甲基苯基氨基甲酸酯)-6-(3,5-二氯苯基氨基甲酸酯)和淀粉2-苯甲酸酯-3-(3,5-二氯苯基氨基甲酸酯)-6-(4-甲基苯基氨基甲酸酯),将二者分别涂覆于氨丙基硅胶后用作液相色谱手性固定相。研究表明:所制备的手性固定相显示出特异的手性识别能力,其手性识别能力明显高于均匀取代淀粉衍生物——淀粉三(3,5-二氯苯基氨基甲酸酯),取代基的性质及在葡萄糖单元上的位置对手性固定相的手性识别能力有较大的影响。一些未在商品化的手性柱Chiralpak AD上得到有效分离的手性化合物在所制备的固定相上得到了更好的分离。所测试的8对对映体在淀粉2-苯甲酸酯-3-(4-甲基苯基氨基甲酸酯)-6-(3,5-二氯苯基氨基甲酸酯)固定相上均得到了分离,因而此固定相的手性识别能力较强,具有潜在的应用价值。     

Comparison of enantiomer separation on two chiral stationary phases derived from (+)-18-crown-6-2,3,11,12-tetracarboxylic acid of the same chiral selector

Liquid chromatographic comparisons for enantiomer resolution of α-amino acids and chiral primary amino compounds were made using chiral stationary phases (CSPs) prepared by covalently bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA) of the same chiral selector. The resolution of all α-amino acids on CSP 1 developed in our group was found to be better than that on CSP 2 reported by Machida et al. All α-amino acids examined in this study were well enantioseparated on CSP 1 (α=1.22–2.47), while four analytes were not resolved or all the other analytes were poorly resolved on CSP 2 than on CSP 1. However, in resolving the primary amino compounds without a carbonyl group, CSP 1 was comparable with CSP 2. Although (+)-18-C-6-TA of the same chiral selector was used to prepare CSP 1 and CSP 2, this study showed that different connecting methods for the CSPs might influence their ability to resolve the analytes depending on their structures related to the chiral recognition mechanism.     

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

Five 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 racemic N-acylarylalkylamines on various amino alcohol derived tau-acidic chiral stationary phases

Five tau-acidic chiral stationary phases (CSPs), CSP 4, CSP 5, CSP 6, CSP 7 and CSP 8, were prepared by connecting the N-(3,5-dimethylbenzoyl) derivative of (R)-alaninol, (S)-leucinol, (1S,2R)-ephedrine and (S)-tert-leucinol and the O-(3,5-dinitrobenzoyl) derivative of (R)-phenylglycinol to silica gel through a carbamate or urea linkage. The CSPs were applied to the resolution of various racemic N-acyl-1-naphthylaminoalkanes by chiral HPLC, and the chromatographic resolution results were compared with those of previously reported CSPs (CSP 2, CSP 3), which are derived from N-(3,5-dinitrobenzoyl)-(1S,2R)-norephedrine and N-(3,5-dinitrobenzoyl-(R)-phenylglycinol. Based on a comparison of the resolution results for each CSP, the role of each functional group on the five chiral selectors is explained.     

外消旋萘普生酯类在(S,S)-Whelk-O1与CDMPC手性柱上的对映体分离及手性识别机理的比较

在Pirkle型的(S,S)-Whelk-O 1与纤维素衍生物型的CDMPC两种手性柱上对六种 外消旋萘普生酯进行了对映体分离，通过研究烷氧基结构上的差异以及流动相中不 同的醇类添加剂对手性识别的影响，探讨和比较了外消旋萘普生酯在两种手性固定 相上手性识别的机理。对于 (S,S)-Whelk-O 1， 溶质与固定相之间的吸引作用于 手性识别的主要因素，而对于CDMPC，溶质在手性空腔中的空间适应性很可能是手 性识别的关键。     

Liquid chromatographic resolution of beta-amino acids on CSPs based on optically active (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6

Two chiral stationary phases (CSPs) based on optically active (3,3′-diphenyl-1,1′-binaphthyl)-20-crown-6 covalently bonded to silica gel were utilized for the first time for the resolution of racemic β-amino acids using high performance liquid chromatography. All of the 10 β-amino acids tested were resolved on the CSP containing residual silanol-protecting n-octyl groups, while only five β-amino acids were resolved on the CSP containing residual silanol groups. The superiority of the CSP containing residual silanol-protecting n-octyl groups and the characteristic retention behaviors of the two enantiomers on the CSP were rationalized to stem from the removal of the residual silanol groups, which can otherwise induce the non-enantioselective retention of the analytes, and the improved lipophilicity of the CSP. The elution orders of the two enantiomers of β-amino acids were identical on the two CSPs and, consequently, it was concluded that the two CSPs were concluded to utilize identical chiral recognition mechanisms. The different elution orders of the analytes were proposed to be attributed to the presence or absence of π-π interactions between the CSP and analytes.     

Intermolecular (1)H-(1)H Two-Dimensional Nuclear Overhauser Enhancements in the Characterization of a Rationally Designed Chiral Recognition System

Chiral stationary phases (CSPs) for liquid chromatography derived from N-(acyl)proline-3,5-dimethylanilides separate the enantiomers of N-(3,5-dinitrobenzoyl)-alpha-amino esters and amides with high levels of selectivity. These CSPs have been used to assemble a large body of chromatographic data which indirectly supports the validity of the mechanistic rationale originally used in the design of these CSPs. We herein report (1)H and (13)C chemical shift data obtained when the (S)-enantiomer of chiral solvating agent (CSA) 3, a soluble analogue of the selector used in CSP (S)-1, acts on each of the enantiomers of the dimethylamide of N-(3,5-dinitrobenzoyl)leucine, 2. The changes in chemical shift in the mixture of (S)-2 and (S)-3 support the existence of those interactions thought to be essential to chiral recognition in this system. In addition, significant intermolecular NOESY enhancements are observed in this mixture. These NOE data are consistent with the structure expected for the more stable diastereomeric adsorbate formed between (S)-2 and the (S)-proline-derived CSP 1. No intermolecular NOEs are observed for corresponding mixtures of the chiral solvating agent (S)-3 and (R)-2, the enantiomer least retained on (S)-CSP 1.