HPLC enantioseparation on cellulose tris(3,5-dimethylphenylcarbamate) as a chiral stationary phase: Influences of pore size of silica gel,coating amount,coating solvent,and column temperature on chiral discrimination

Cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) was coated on large-pore silica gels and used as a chiral stationary phase (CSP) for high-performance liquid chromatographic separation of enantiomers. The influences of pore size of silica gel, coating amount of CDMPC, coating solvent, and column temperature on chiral discrimination were investigated. CSPs prepared with a large-pore silica gel having a small surface area showed higher chiral recognition. The amount of CDMPC adsorbed on the silica gel influenced the chiral recognition of some racemates. Loading capacity of racemates increased with an increase of the amount of CDMPC supported on the silica gel, and a CSP coated with 45% CDMPC by weight can be used for both analytical and semi-preparative scale separations. The CDMPC, coated using acetone as the coating solvent, exhibited, in many cases, higher enantioselectivity than that obtained with tetrahydrofuran F as the coating solvent. © 1996 Wiley-Liss, Inc.     

Synthesis and Enantioseparation Ability of Xylan Bisphenylcarbamate Derivatives as Chiral Stationary Phases in HPLC

Ten novel xylan bisphenylcarbamate derivatives bearing meta‐ and para‐substituents on their phenyl groups were synthesized and their chiral recognition abilities were evaluated as the chiral stationary phases (CSPs) for high‐performance liquid chromatography (HPLC) after coating them on macroporous silica. The chiral recognition abilities of these CSPs depended on the nature, position, and number of the substituents on the phenyl moieties. The introduction of an electron‐donating group was more attractive than an electron‐withdrawing group to improve the chiral recognition ability of the xylan phenylcarbamate derivatives. Among the CSPs discussed in this study, xylan bis(3,5‐dimethylphenylcarbamate)‐based CSP seems to possess the highest resolving power for many racemates, and the meta‐substituted CSPs showed relatively better chiral recognition than the para‐substituted ones. For some racemates, the xylan bis(3,5‐dimethylphenylcarbamate) derivative exhibited higher enantioselectivity than the CSP based on cellulose tris(3,5‐dimethylphenylcarbamate). Chirality 27:518–522, 2015 © 2015 Wiley Periodicals, Inc.     

Functionalities tuned enantioselectivity of phenylcarbamate cyclodextrin clicked chiral stationary phases in HPLC

The mixed chloro‐ and methyl‐ functionalities can greatly modulate the enantioselectivities of phenylcarbamate cyclodextrin (CD) clicked chiral stationary phases (CSPs). A comparison study is herein reported for per(4‐chloro‐3‐methyl)phenylcarbamate and per(2‐chloro‐5‐methyl)phenylcarbamate β‐CD clicked CSPs (i.e., CCC4M3‐CSP and CCC2M5‐CSP). The enantioselectivity dependence on column temperature was studied in both normal‐phase and reversed‐phase mode high performance liquid chromatography (HPLC). The thermodynamic study revealed that the stronger intermolecular interactions can be formed between CCC4M3‐CSP and chiral solutes to drive the chiral separation. The higher enantioselectivities of CCC4M3‐CSP were further demonstrated with the enantioseparation of 17 model racemates in HPLC.     

Direct HPLC enantioseparation of chiral aptazepine derivatives on coated and immobilized polysaccharide-based chiral stationary phases

The direct HPLC enantioseparation of Mianserin and a series of aptazepine derivatives is accomplished on polysaccharide-based chiral stationary phases (CSPs). The resolutions are performed on the coated-type Chiralcel OD and Chiralpak AD CSPs and on the first commercially available immobilized-type Chiralpak IA CSP, in normal-phase and polar-organic modes. The complete separation of enantiomers of all racemates investigated was successfully achieved under at least one of CSP/eluent combinations employed. Pure alcohols such ethanol or 2-propanol, with a fixed percentage of DEA added, serve as valuable alternatives to the more common n-hexane-based normal-phase eluents in resolution of Mianserin on the AD CSP. In order to study the chiroptical properties of aptazepine derivatives, chromatographic resolutions are carried out at semipreparative scale using Chiralpak AD and Chiralpak IA as CSPs. Nonconventional dichloromethane-based eluents have permitted to expand the chiral resolving ability of the immobilized Chiralpak IA CSP and to perform mg-scale enantioseparations with an analytical-size column. Assignment of the absolute configuration of the separated enantiomers is empirically established by comparing their chiroptical data with those of structurally related Mianserin.     

Enantioseparation and molecular modeling study of chiral amines as three naphthaldimine derivatives using amylose or cellulose trisphenylcarbamate chiral stationary phases

This study describes the enantioseparation of three chiral amines as naphthaldimine derivatives, using normal phase HPLC with amylose and cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phases (CSPs). Three chiral amines were derivatized using three structurally similar naphthaldehyde derivatizing agents, and the enantioselectivity of the CSPs toward the derivatives was examined. The degree of enantioseparation and resolution was affected by the amylose or cellulose-derived CSPs and aromatic moieties as well as a kind of chiral amine. Especially, efficient enantiomer separation was observed for 2-hydroxynapthaldimine derivatives on cellulose-derived CSPs. Molecular docking studies of three naphthaldimine derivatives of leucinol on cellulose tris(3,5-dimethylphenylcarbamate) were performed to estimate the binding energies and conformations of the CSP–analyte complexes. The obtained binding energies were in good agreement with the experimentally determined enantioseparation and elution order.     

Liquid Chromatographic Resolution of Mexiletine and Its Analogs on Crown Ether‐Based Chiral Stationary Phases

Mexiletine, an effective class IB antiarrhythmic agent, and its analogs were resolved on three different crown ether‐based chiral stationary phases (CSPs), one (CSP 1 ) of which is based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid and the other two (CSP 2 and CSP 3 ) are based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6. Mexiletine was resolved with a resolution (R_S) of greater than 1.00 on CSP 1 and CSP 3 containing residual silanol group‐protecting n‐octyl groups on the silica surface, but with a resolution (R_S) of less than 1.00 on CSP 2 . The chromatographic behaviors for the resolution of mexiletine analogs containing a substituted phenyl group at the chiral center on the three CSPs were quite dependent on the phenoxy group of analytes. Namely, mexiletine analogs containing 2,6‐dimethylphenoxy, 3,4‐dimethylphenoxy, 3‐methylphenoxy, 4‐methylphenoxy, and a simple phenoxy group were resolved very well on the three CSPs even though the chiral recognition efficiencies vary with the CSPs. However, mexiletine analogs containing 2‐methylphenoxy group were not resolved at all or only slightly resolved. Among the three CSPs, CSP 3 was found to show the highest chiral recognition efficiencies for the resolution of mexiletine and its analogs, especially in terms of resolution (R_S). Chirality 26:272–278, 2014. © 2014 Wiley Periodicals, Inc.     

Liquid chromatographic resolution of 3-amino-1,4-benzodiazepin-2-ones on crown ether-based chiral stationary phases

3-Amino-5-phenyl (or 5-methyl)-1,4-benzodiazepin-2-ones, which are chiral precursors of anti-respiratory syncytial virus active agents, were resolved on three different chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid or (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Among the three CSPs, the CSP that is based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 and containing residual silanol group-protecting n-octyl groups on the silica surface was found to be most effective with the use of 80% ethanol in water containing perchloric acid (10 mM) and ammonium acetate (1.0 mM) as a mobile phase. The separation factors (α) and resolutions (R(S) ) were in the range of 1.90-3.21 and 2.79-5.96, respectively. From the relationship between the analyte structure and the chromatographic resolution behavior, the chiral recognition mechanism on the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was proposed to be different from that on the CSP based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. In addition, the chromatographic resolution behavior of the most effective CSP was investigated as a function of the composition of aqueous mobile phase containing organic and acidic modifier and ammonium acetate.     

Enantiomeric discrimination of pyrethroic acid esters on polysaccharide derived chiral stationary phases

Enantiomeric separation of pyrethroic acid methyl and ethyl esters was examined on cellulose-based chiral stationary phases (CSPs): chiralcel OD (cellulose tris(3,5-dimethylphenyl carbamate)) and chiralcel OF (cellulose tris(4-chlorophenyl carbamate)). The good resolution of pyrethroic acid esters was achieved on chiralcel OD and OF. Separation factors ranged from 1.19-5.12 for Chiralcel OD and 1.00-1.59 for chiralcel OF. Hexane/2-propanol (100:0.15, v/v %) was used as the eluent. The resolution capability of CSPs was greater chiralcel OD than chiralcel OF in the case of the pyrethroic acid esters. The flow rate was 0.8 ml/min and detection was set at 230 nm. The results of the chromatographic data and molecular mechanics suggest that steric effect was a major factor in the enantioseparation. Furthermore, the hydrogen bond between analytes and CSP played an important role in the chiral recognition.     

HPLC and SFC enantioseparation of (±)‐Corey lactone diol: Impact of the amylose tris‐(3,5‐dimethylphenylcarbamate) coating amount on chiral preparation

As an important intermediate of prostaglandins and entecavir, optically pure Corey lactone diol (CLD) has great value in the pharmaceutical industry. In this work, the enantioseparation of (±)‐CLD was evaluated using high‐performance liquid (HPLC) and supercritical fluid chromatography (SFC). In HPLC, the separations of CLD enantiomers on polysaccharide‐based chiral stationary phases with both normal phase and polar organic phase were screened. And the conditions for the enantioseparation were optimized in HPLC and SFC, including the selection of mobile phase, temperature, back‐pressure, and other conditions. More important, it was found that the chiral resolutions were greatly enhanced by the increase of the coating amount of ADMPC (amylose tris‐(3,5‐dimethylphenylcarbamate)) under both HPLC and SFC conditions, which can lead to the increase of the productivity and the decrease of the solvent consumption. The preparations of optically pure CLD were evaluated on a semi‐preparative (2 × 25 cm) column packed with 30% ADMPC‐coated CSP under HPLC and SFC conditions. Preparative performances in terms of kkd are 1.536 kg racemate/kg CSP/day and 1.248 kg racemate/kg CSP/day in HPLC and SFC, respectively.     

Synthesis and Application of C2 and C3 Symmetric (R)‐Phenylglycinol‐Derived Chiral Stationary Phases

A C3 symmetric (R)‐phenylglycinol N‐1,3,5‐benzenetricarboxylic acid‐derived chiral stationary phase (CSP) and three C2 symmetric (R)‐phenylglycinol CSPs were newly synthesized using o‐, m‐, and p‐phthaloyl dichlorides. © 2016 Wiley Periodicals, Inc. These CSPs were used to compare the resolution of 25 chiral samples using a previously reported 3,5‐dinitrobenzoyl (R)‐phenylglycinol‐derived CSP. Even though all CSPs have the same chiral moiety, the C3 symmetric CSP showed the best resolution. Chirality 28:186–191, 2016.© 2016 Wiley Periodicals, Inc.     

Chromatographic properties of composite chiral stationary phases based on cellulose derivatives

Chiral stationary phases (CSPs) prepared by mixing together two different cellulose derivatives, before or after being coated on macroporous silica gel, were developed in order to determine the mutual influence of two different polymers on global chiral recognition capacity. The chromatographic properties of these CSPs were evaluated using a wide range of racemic test solutes. The mixing method does not significantly affect the enantioselectivities. The composite CSPs obtained by cocoating of two different cellulose derivatives on silica generally exhibit chiral recognition capacities intermediate between those of the two individual phases, and thus broadening the application range of a single column. These results indicate that the simultaneous coating of two different cellulose derivatives does not significantly alter the optical resolution power of each chiral material and are discussed in relationship with the supramolecular structure of the polymeric stationary phases. © 1995 Wiley-Liss, Inc.     

Chiral stationary phases in HPLC for the stereoselective determination of methadone

An extensive study of the behavior of three chiral stationary phases (CSP) used in liquid chromatography (LC) is presented for the stereoselective determination of methadone. The following chromatographic columns were selected: a cellulose, Chiralcel OJ; a modified cyclodextrin, Cyclobond I 2000 RSP, and a protein, Chiral‐AGP. Retention factors, enantioselectivity, efficiency, and resolution were tested by modifying the composition of the mobile phase as well as the temperature. The mechanism for the chiral recognition of methadone on each support was discussed. Optimal chromatographic parameters were obtained for the three supports tested, and methadone enantiomers were separated in less than 20 minutes. The cellulose‐based column gave the best resolution, but this CSP was not adapted to clinical analyses of methadone. Under optimized conditions, the cyclodextrin‐ and protein‐based columns allowed an excellent separation of methadone enantiomers, but no interference with the primary metabolite was found only with Chiral‐AGP. Chirality 11:319–325, 1999. © 1999 Wiley‐Liss, Inc.     

Nanocellulose 3, 5‐Dimethylphenylcarbamate Derivative Coated Chiral Stationary Phase: Preparation and Enantioseparation Performance

Nanocrystalline cellulose (NCC) with high surface area and high ordered crystalline structure was prepared from microcrystalline cellulose (MCC) under the hydrolysis of sodium hypochlorite. NCC was further reacted with 3,5‐dimethylphenyl isocyanate to obtain the nanocellulose derivative, and then coated successfully on the surface of silica gel to a prepared NCC‐coated chiral stationary phase (CSP) as a new kind of chiral separation material. Similarly, MCC derivative‐coated CSP was also prepared as contrast. The chiral separation performance of NCC‐based CSP was evaluated and compared with MCC‐based CSP by high‐performance liquid chromatography. Moreover, the effects of the alcohol modifiers, mobile phase additives, and flow rates on chiral separations were investigated in detail. The results showed that 10 chiral compounds were separated on NCC‐based CSP with better peak shape and higher column efficiency than MCC‐based CSP, which confirmed that NCC‐based CSP was a promising packing material for the resolution of chiral compounds.Chirality 28:376–381, 2016. © 2016 Wiley Periodicals, Inc.     

Synthesis of new C3 symmetric amino acid‐ and aminoalcohol‐containing chiral stationary phases and application to HPLC enantioseparations

We recently reported a new C3‐symmetric (R)‐phenylglycinol N‐1,3,5‐benzenetricarboxylic acid‐derived chiral high‐performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N‐3,5‐dintrobenzoyl (DNB) (R)‐phenylglycinol‐derived CSP. Over a decade ago, (S)‐leucinol, (R)‐phenylglycine, and (S)‐leucine derivatives were used as the starting materials of 3,5‐DNB‐based Pirkle‐type CSPs for chiral separation. In this study, three new C3‐symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3‐symmetric CSPs (CSP 2–CSP 4).     

Optical resolution of alpha-alkyl phenyl acetonitriles by HPLC on cellulose triacetate chiral stationary phases coated on underivatized silica gel

Microcrystalline celluloses from two sources were used to prepare cellulose triacetate chiral stationary phases (CSPs) coated on underivatized silica gel, which shows discriminating chiral recognition for enantiomers. The chiral separation of four alpha-alkyl phenyl acetonitriles was investigated on the prepared CSPs. It was observed that the concentration of the coating solvent of phenol in dichloromethane plays an important role in the resolution of the solutes. A series of primary alcohols, including secondary and tertiary alcohols, were used as mobile phase modifiers to investigate the effect of the structures of these modifiers on the capacity factors (k') and the separation factors (alpha). Also, the effect of the concentration of alcohol on the capacity factors and separation factors was examined. The chiral recognition mechanism of alpha-alkyl phenyl acetonitriles on the prepared CSPs is discussed. Copyright 2000 Wiley-Liss, Inc.     

Enantioresolution of Chiral Derivatives of Xanthones on (S,S)‐Whelk‐O1 and l‐Phenylglycine Stationary Phases and Chiral Recognition Mechanism by Docking Approach for (S,S)‐Whelk‐O1

The resolution of seven enantiomeric pairs of chiral derivatives of xanthones (CDXs) on (S,S)‐Whelk‐O1 and l ‐phenylglycine chiral stationary phases (CSPs) was systematically investigated using multimodal elution conditions (normal‐phase, polar‐organic, and reversed‐phase). The (S,S)‐Whelk‐O1 CSP, under polar‐organic conditions, demonstrated a very good power of resolution for the CDXs possessing an aromatic moiety linked to the stereogenic center with separation factor and resolution factor ranging from 1.91 to 7.55 and from 6.71 to 24.16, respectively. The chiral recognition mechanisms were also investigated for (S,S)‐Whelk‐O1 CSP by molecular docking technique. Data regarding the CSP–CDX molecular conformations and interactions were retrieved. These results were in accordance with the experimental chromatographic parameters regarding enantioselectivity and enantiomer elution order. The results of the present study fulfilled the initial objectives of enantioselective studies of CDXs and elucidation of intermolecular CSP–CDX interactions. Chirality 25:89–100, 2013. © 2012 Wiley Periodicals, Inc.     

Development of HPLC Chiral Stationary Phases Based on (+)‐(18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid and Their Applications

Crown ether‐based chiral stationary phases (CSPs) have been known to be useful for the resolution of racemic primary amino compounds. In particular, CSPs based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid have been reported to be useful for the resolution of secondary amino compounds as well as primary amino compounds. In this article, the process of developing various CSPs based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid to improve the chiral recognition efficiency and/or the stability of the CSPs and their applications to the resolution of various primary and nonprimary amino compounds are reviewed. Chirality 27:576–588, 2015. © 2015 Wiley Periodicals, Inc.     

Synthesis and HPLC chiral recognition of regioselectively carbamoylated cellulose derivatives

Four regioselective-carbamoylated cellulose derivatives having two different substituents at 2-, 3-, and 6-position were prepared and evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography. Investigations showed that the nature and arrangement of the substituents significantly influenced the chiral recognition abilities of the heterosubstituted cellulose derivatives and each derivative exhibited characteristic enantioseparation. Some racemates were better resolved on these derivatives than the corresponding homogeneously substituted cellulose derivatives including a commercial CSP, Chiralcel OD. Racemic compounds shown in this study were most effectively discriminated on cellulose 2,3-(3-chloro-4-methylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate) and 2,3-(3,5-dimethylphenylcarbamate)-6-(3-chloro-4-methylphenylcarbamate).     

Separation of nicotine and nornicotine enantiomers via normal phase HPLC on derivatized cellulose chiral stationary phases

This paper describes the enantiorecognition of (±)nicotine and (±)nornicotine by high-performance liquid chromatography using two derivatized cellulose chiral stationary phases (CSPs) operated in the normal phase mode. It was found that different substituents linked to the cellulose backbone significantly influence the chiral selectivity of the derivatized CSP. The results showed that, in general, the tris(4-methylbenzoyl) cellulose CSP (Chiralcel OJ) surpasses tris(3,5-dimethylphenyl carbamoyl) cellulose CSP (Chiralcel OD). On the former column, the resolution (±)nicotine and (±)nornicotine enantiomers depended largely on mobile phase compositions. For the separation of the nicotine enantiomers, the addition of trifluoroacetic acid to a 95:5 hexane/alcohol mobile phase greatly improved the enantioresolution, probably due to enhanced hydrogen bonding interactions between the protonated analytes and the CSP. For (±)nornicotine separation, a reduction in the concentration of alcohol in the mobile phase was more effective than the addition of trifluoroacetic acid. Possible solute-mobile phase-stationary phase interactions are discussed to explain how different additives in the mobile phase and different substituents on the cellulose glucose units of the CSPs affect the separation of both pairs of enantiomers. Chirality 10:364–369, 1998. Published 1998 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds

The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO₂) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO₂). Then, the GO@SiO₂ was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO₂), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO₂ to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene‐enriched enantiomers were separated completely, and the resolution of trans‐stilbene oxide perfectly reached 4.83. Compared with the blank column of non‐bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π‐π stacking, hydrophobic effect, π‐π electron‐donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene‐enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.