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1230 KiB

Open AccessArticle

Preparative Scale Resolution of Enantiomers Enables Accelerated Drug Discovery and Development

by Hanna Leek and Shalini Andersson

Molecules 2017, 22(1), 158; https://doi.org/10.3390/molecules22010158 - 18 Jan 2017

Cited by 49 | Viewed by 7216

Abstract

The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such [...] Read more.

The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca. The combination of chromatography and racemization as well as strategies on when to apply preparative chiral chromatography of enantiomers in a multi-step synthesis of a drug compound can further facilitate accelerated drug discovery and the early clinical evaluation of the drug candidates. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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2665 KiB

Open AccessArticle

Achiral Molecular Recognition of Aromatic Position Isomers by Polysaccharide-Based CSPs in Relation to Chiral Recognition

by Tohru Shibata, Satoshi Shinkura, Atsushi Ohnishi and Kazuyoshi Ueda

Molecules 2017, 22(1), 38; https://doi.org/10.3390/molecules22010038 - 28 Dec 2016

Cited by 15 | Viewed by 5649

Abstract

Chromatographic separation of several sets of aromatic position isomers on three cellulose- and one amylose-based chiral stationary phases was performed to evaluate the potential of a polysaccharide-based chiral stationary phase (CSP) in the separation of isomeric or closely similar molecules, and to understand [...] Read more.

Chromatographic separation of several sets of aromatic position isomers on three cellulose- and one amylose-based chiral stationary phases was performed to evaluate the potential of a polysaccharide-based chiral stationary phase (CSP) in the separation of isomeric or closely similar molecules, and to understand the interaction mechanism of this type of CSP with analytes. Their ability of molecular recognition was quite outstanding, but the selection rule was particular to each polysaccharide derivative. In the series of analytes, cellulose tris(4-methylbenzoate) and tris(3,5-dimethylphenylcarbamate) exhibited a contrasting selection rule, and the recognition mechanism was considered based on the computer-simulation of the former polymer. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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2866 KiB

Open AccessArticle

Photochemically Immobilized 4-Methylbenzoyl Cellulose as a Powerful Chiral Stationary Phase for Enantioselective Chromatography

by Eric Francotte, Dan Huynh and Tong Zhang

Molecules 2016, 21(12), 1740; https://doi.org/10.3390/molecules21121740 - 17 Dec 2016

Cited by 14 | Viewed by 4822

Abstract

A process to immobilize para-methylbenzoyl cellulose (PMBC) on silica gel has been developed and applied to prepare chiral stationary phases (CSPs) for enantioselective chromatography. The immobilization was achieved by simple irradiation of the polysaccharide derivative with ultraviolet light after coating on a [...] Read more.

A process to immobilize para-methylbenzoyl cellulose (PMBC) on silica gel has been developed and applied to prepare chiral stationary phases (CSPs) for enantioselective chromatography. The immobilization was achieved by simple irradiation of the polysaccharide derivative with ultraviolet light after coating on a silica gel support. The influence of parameters such as irradiation time and solvent on immobilization effectiveness were investigated. The performance of the prepared immobilized phases were evaluated by injection of a series of racemic compounds onto the packed columns and determination of their chiral recognition ability. By contrast to the classical coated phase, the immobilized CSP can be used under various chromatographic conditions without limitation of organic solvent types as the mobile phase. This extended applicability permits to improve selectivity and to resolve chiral compounds which are not or only poorly soluble in the mobile phases which are compatible with the non-immobilized PMBC stationary phase. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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967 KiB

Open AccessArticle

A Novel Two-Step Liquid-Liquid Extraction Procedure Combined with Stationary Phase Immobilized Human Serum Albumin for the Chiral Separation of Cetirizine Enantiomers along with M and P Parabens

by Aleksandra Chmielewska, Lucyna Konieczna and Tomasz Bączek

Molecules 2016, 21(12), 1654; https://doi.org/10.3390/molecules21121654 - 7 Dec 2016

Cited by 7 | Viewed by 6819

Abstract

The research into the separation of drug enantiomers is closely related to the safety and efficiency of the drugs. The aim of this study was to develop a simple and validated HPLC method to analyze cetirizine enantiomers. In the case of liquid dosage [...] Read more.

The research into the separation of drug enantiomers is closely related to the safety and efficiency of the drugs. The aim of this study was to develop a simple and validated HPLC method to analyze cetirizine enantiomers. In the case of liquid dosage forms, besides the active substance in large amounts there are usually also inactive ingredients such as methyl- and propylparaben. Unfortunately, these compounds can interfere with the analyte, inter alia during chiral separation of the analyte enantiomers. The proposed innovative two-step liquid-liquid extraction procedure allowed for the determination of cetirizine enantiomers (along with M and P parabens) also in liquid dosage forms. The main focus of this study was the chromatographic activity of cetirizine dihydrochloride on the proteinate-based chiral stationary phase. The chromatographic separation of cetirizine enantiomers was performed on an immobilized human serum albumin (HSA) column for the first time. Measurements were performed at a wavelength of 227 nm. Under optimal conditions, baseline separation of two enantiomers was obtained with 1.43 enantioseparation factor (α) and 1.82 resolution (R_s). Finally, the proposed method was successfully applied to the selected pharmaceutical formulations. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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3898 KiB

Open AccessArticle

A Comparative Study of Enantioseparations of N^α-Fmoc Proteinogenic Amino Acids on Quinine-Based Zwitterionic and Anion Exchanger-Type Chiral Stationary Phases under Hydro-Organic Liquid and Subcritical Fluid Chromatographic Conditions

by Gyula Lajkó, Nóra Grecsó, Gábor Tóth, Ferenc Fülöp, Wolfgang Lindner, Antal Péter and István Ilisz

Molecules 2016, 21(11), 1579; https://doi.org/10.3390/molecules21111579 - 22 Nov 2016

Cited by 11 | Viewed by 7117

Abstract

The focus of this contribution is a comparative investigation of enantioseparations of 19 N^α-Fmoc proteinogenic amino acids on Quinine-based zwitterionic and anion-exchanger type chiral stationary phases employing hydro-organic and polar-ionic liquid and subcritical fluid chromatographic conditions. Effects of mobile phase [...] Read more.

The focus of this contribution is a comparative investigation of enantioseparations of 19 N^α-Fmoc proteinogenic amino acids on Quinine-based zwitterionic and anion-exchanger type chiral stationary phases employing hydro-organic and polar-ionic liquid and subcritical fluid chromatographic conditions. Effects of mobile phase composition (including additives, e.g., water, basis and acids) and nature of chiral selectors on the chromatographic performances were studied at different chromatographic modes. Thermodynamic parameters of the temperature dependent enantioseparation results were calculated in the temperature range 5–50 °C applying plots of lnα versus 1/T. The differences in standard enthalpy and standard entropy for a given pair of enantiomers were calculated and served as a basis for comparisons. Elution sequence in all cases was determined, where a general rule could be observed, both in liquid and subcritical fluid chromatographic mode the d-enantiomers eluted before the L ones. In both modes, the principles of ion exchange chromatography apply. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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3661 KiB

Open AccessArticle

Temperature-Triggered Switchable Helix-Helix Inversion of Poly(phenylacetylene) Bearing l-Valine Ethyl Ester Pendants and Its Chiral Recognition Ability

by Yanli Zhou, Chunhong Zhang, Yuan Qiu, Lijia Liu, Taotao Yang, Hongxing Dong, Toshifumi Satoh and Yoshio Okamoto

Molecules 2016, 21(11), 1583; https://doi.org/10.3390/molecules21111583 - 21 Nov 2016

Cited by 21 | Viewed by 6076

Abstract

A phenylacetylene containing the l-valine ethyl ester pendant (PAA-Val) was synthesized and polymerized by an organorhodium catalyst (Rh(nbd)BPh₄) to produce the corresponding one-handed helical cis-poly(phenylacetylene) (PPAA-Val). PPAA-Val showed a unique temperature-triggered switchable helix-sense in chloroform, while it was not [...] Read more.

A phenylacetylene containing the l-valine ethyl ester pendant (PAA-Val) was synthesized and polymerized by an organorhodium catalyst (Rh(nbd)BPh₄) to produce the corresponding one-handed helical cis-poly(phenylacetylene) (PPAA-Val). PPAA-Val showed a unique temperature-triggered switchable helix-sense in chloroform, while it was not observed in highly polar solvents, such as N,N′-dimethylformamide (DMF). By heating the solution of PPAA-Val in chloroform, the sign of the CD absorption became reversed, but recovered after cooling the solution to room temperature. Even after six cycles of the heating-cooling treatment, the helix sense of the PPAA-Val’s backbone was still switchable without loss of the CD intensity. The PPAA-Val was then coated on silica gel particles to produce novel chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). These novel PPAA-Val based CSPs showed a high chiral recognition ability for racemic mandelonitrile (α = 2.18) and racemic trans-N,N′-diphenylcyclohexane-1,2-dicarboxamide (α = 2.60). Additionally, the one-handed helical cis-polyene backbone of PPAA-Val was irreversibly destroyed to afford PPAA-Val-H by heating in dimethyl sulfoxide (DMSO) accompanied by the complete disappearance of the Cotton effect. Although PPAA-Val-H had the same l-valine ethyl ester pendants as its cis-isomer PPAA-Val, it showed no chiral recognition. It was concluded that the one-handed helical cis-polyene backbone of PPAA-Val plays an important role in the chiral recognition ability. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1825 KiB

Open AccessCommunication

Direct Separation of Pregabalin Enantiomers Using a Zwitterionic Chiral Selector by High Performance Liquid Chromatography Coupled to Mass Spectrometry and Ultraviolet Detection

by Lakshmi Narayana Chennuru, Thirupathi Choppari, Ramakrishna Prasad Nandula, Tong Zhang and Pilar Franco

Molecules 2016, 21(11), 1578; https://doi.org/10.3390/molecules21111578 - 19 Nov 2016

Cited by 14 | Viewed by 7233

Abstract

The chromatographic resolution of pregabalin enantiomers has been often achieved by derivatization of the molecule, in order to reach enough sensitivity at low concentrations of the minor enantiomer present in the active principle. In the present article, the development and optimization of two [...] Read more.

The chromatographic resolution of pregabalin enantiomers has been often achieved by derivatization of the molecule, in order to reach enough sensitivity at low concentrations of the minor enantiomer present in the active principle. In the present article, the development and optimization of two liquid chromatographic methods are presented for the direct resolution of pregabalin enantiomers on a chiral stationary phase (CSP) containing a zwitterionic selector derived from cinchona alkaloid and sulfonic acid (CHIRALPAK ZWIX). The key parameters for the separation as well as the compatibility of chromatographic conditions with different detection modes (ultraviolet and mass spectrometry) were investigated. The resulting methods were found to be selective, of high performance and low limits of detection (2 µg/mL by UV and 1 ng/mL by MS, respectively) and quantification (6 µg/mL by UV and 5 ng/mL by MS, respectively) for the minor enantiomer which is considered as a chiral impurity. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1628 KiB

Open AccessCommunication

Photo Racemization and Polymerization of (R)-1,1′-Bi(2-naphthol)

by Zhaoming Zhang, Yue Wang and Tamaki Nakano

Molecules 2016, 21(11), 1541; https://doi.org/10.3390/molecules21111541 - 16 Nov 2016

Cited by 16 | Viewed by 7760

Abstract

(R)-1,1’-Bi(2-naphthol) ((R)-BINOL) in an acetonitrile solution lost optical activity upon irradiation with an Hg–Xe lamp. HPLC resolution of the product indicated that (R)-BINOL was racemized upon irradiation, and SEC analysis suggested that a polymeric product was formed [...] Read more.

(R)-1,1’-Bi(2-naphthol) ((R)-BINOL) in an acetonitrile solution lost optical activity upon irradiation with an Hg–Xe lamp. HPLC resolution of the product indicated that (R)-BINOL was racemized upon irradiation, and SEC analysis suggested that a polymeric product was formed in the course of racemization. It is proposed that polymerization of BINOL can occur before it is racemized and that a unit in a polymer derived from BINOL may lose its optical activity afterwards due to in-chain racemization and/or reduction. The polymeric products seem to consist not only of BINOL residues but also of residues derived from acetonitrile as well as those derived through reduction of BINOL. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1768 KiB

Open AccessArticle

Development of Amylose- and β-Cyclodextrin-Based Chiral Fluorescent Sensors Bearing Terthienyl Pendants

by Tomoyuki Ikai, Changsik Yun, Yutaka Kojima, Daisuke Suzuki, Katsuhiro Maeda and Shigeyoshi Kanoh

Molecules 2016, 21(11), 1518; https://doi.org/10.3390/molecules21111518 - 11 Nov 2016

Cited by 11 | Viewed by 6284

Abstract

Phenylcarbamate derivatives of amylose and β-cyclodextrin show excellent chiral recognition when used as chiral stationary phases (CSPs) for high-performance liquid chromatography. To open up new possibilities of carbohydrate-based materials, we developed chiral fluorescent sensors based on amylose and β-cyclodextrin (Am-1b and CyD- [...] Read more.

Phenylcarbamate derivatives of amylose and β-cyclodextrin show excellent chiral recognition when used as chiral stationary phases (CSPs) for high-performance liquid chromatography. To open up new possibilities of carbohydrate-based materials, we developed chiral fluorescent sensors based on amylose and β-cyclodextrin (Am-1b and CyD-1b, respectively) by attaching fluorescent π-conjugated units on their side chains. Their recognition abilities toward chiral analytes containing a nitrophenyl unit were evaluated by measuring the enantioselective fluorescence quenching behavior. Both sensors showed the same degree of enantioselective fluorescence response for various aromatic nitro compounds. However, in some cases, their enantioselectivities were different depending on the analytes. The difference in the chiral recognition abilities between Am-1b and CyD-1b seems to be based on the structural difference of their inherent backbones, that is, the one-handed helical structure and cyclic structure, respectively. The study on the resolution ability of the Am-1b-based CSP revealed that the terthienyl-based pendant of Am-1b provides not only a fluorescent functionality but also a different chiral recognition site from that of amylose tris(phenylcarbamate). Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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885 KiB

Open AccessArticle

Enantioselective Analytical- and Preparative-Scale Separation of Hexabromocyclododecane Stereoisomers Using Packed Column Supercritical Fluid Chromatography

by Nicole Riddell, Lauren Gayle Mullin, Bert Van Bavel, Ingrid Ericson Jogsten, Alan McAlees, Allison Brazeau, Scott Synnott, Alan Lough, Robert McCrindle and Brock Chittim

Molecules 2016, 21(11), 1509; https://doi.org/10.3390/molecules21111509 - 10 Nov 2016

Cited by 7 | Viewed by 6367

Abstract

Hexabromocyclododecane (HBCDD) is an additive brominated flame retardant which has been listed in Annex A of the Stockholm Convention for elimination of production and use. It has been reported to persist in the environment and has the potential for enantiomer-specific degradation, accumulation, or [...] Read more.

Hexabromocyclododecane (HBCDD) is an additive brominated flame retardant which has been listed in Annex A of the Stockholm Convention for elimination of production and use. It has been reported to persist in the environment and has the potential for enantiomer-specific degradation, accumulation, or both, making enantioselective analyses increasingly important. The six main stereoisomers of technical HBCDD (i.e., the (+) and (−) enantiomers of α-, β-, and γ-HBCDD) were separated and isolated for the first time using enantioselective packed column supercritical fluid chromatography (pSFC) separation methods on a preparative scale. Characterization was completed using published chiral liquid chromatography (LC) methods and elution profiles, as well as X-ray crystallography, and the isolated fractions were definitively identified. Additionally, the resolution of the enantiomers, along with two minor components of the technical product (δ- and ε-HBCDD), was investigated on an analytical scale using both LC and pSFC separation techniques, and changes in elution order were highlighted. Baseline separation of all HBCDD enantiomers was achieved by pSFC on an analytical scale using a cellulose-based column. The described method emphasizes the potential associated with pSFC as a green method of isolating and analyzing environmental contaminants of concern. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1708 KiB

Open AccessArticle

Enantioseparation Using Cellulose Tris(3,5-dimethylphenylcarbamate) as Chiral Stationary Phase for HPLC: Influence of Molecular Weight of Cellulose

by Yuji Okada, Chiyo Yamamoto, Masami Kamigaito, Yuan Gao, Jun Shen and Yoshio Okamoto

Molecules 2016, 21(11), 1484; https://doi.org/10.3390/molecules21111484 - 8 Nov 2016

Cited by 24 | Viewed by 6463

Abstract

The cellulose oligomers with different degrees of polymerization (DP), 7, 11, 18, 24, 26, 40 and 52, were prepared by hydrolysis of microcrystalline cellulose with phosphoric acid. These oligomers including the starting microcrystalline cellulose (DP 124) were converted to tris(3,5-dimethylphenylcarbamate) (CDMPC) derivatives by [...] Read more.

The cellulose oligomers with different degrees of polymerization (DP), 7, 11, 18, 24, 26, 40 and 52, were prepared by hydrolysis of microcrystalline cellulose with phosphoric acid. These oligomers including the starting microcrystalline cellulose (DP 124) were converted to tris(3,5-dimethylphenylcarbamate) (CDMPC) derivatives by the reaction with an excess of 3,5-dimethylphenyl isocyanate to be used as the chiral stationary phase (CSP) in high-performance liquid chromatography (HPLC). The structures of the CDMPC derivatives were investigated by infrared spectroscopy (IR), ¹H-NMR, circular dichroism (CD) and size exclusion chromatography (SEC), and the DPs of the derivatives estimated by SEC agreed with those estimated by ¹H-NMR. After coating the derivatives on silica gel, their chiral recognition abilities were evaluated using eight racemates under a normal phase condition with a hexane-2-propanol (99/1) mixture as an eluent. The chiral recognition abilities of 7- and 11-mers, particularly the former, were lower than those of the higher oligomers from DP 18 to 52, which had rather similar abilities to that of 124-mer, although the abilities depended on the racemates. DP 18 seems to be sufficient for CDMPC to exhibit chiral recognition similar to that of the CDMPC with larger DPs. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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2578 KiB

Open AccessArticle

Application of Homochiral Alkylated Organic Cages as Chiral Stationary Phases for Molecular Separations by Capillary Gas Chromatography

by Shengming Xie, Junhui Zhang, Nan Fu, Bangjin Wang, Cong Hu and Liming Yuan

Molecules 2016, 21(11), 1466; https://doi.org/10.3390/molecules21111466 - 8 Nov 2016

Cited by 17 | Viewed by 6444

Abstract

Molecular organic cage compounds have attracted considerable attention due to their potential applications in gas storage, catalysis, chemical sensing, molecular separations, etc. In this study, a homochiral pentyl cage compound was synthesized from a condensation reaction of (S,S)-1,2-pentyl-1,2-diaminoethane and [...] Read more.

Molecular organic cage compounds have attracted considerable attention due to their potential applications in gas storage, catalysis, chemical sensing, molecular separations, etc. In this study, a homochiral pentyl cage compound was synthesized from a condensation reaction of (S,S)-1,2-pentyl-1,2-diaminoethane and 1,3,5-triformylbenzene. The imine-linked pentyl cage diluted with a polysiloxane (OV-1701) was explored as a novel stationary phase for high-resolution gas chromatographic separation of organic compounds. Some positional isomers were baseline separated on the pentyl cage-coated capillary column. In particular, various types of enantiomers including chiral alcohols, esters, ethers and epoxides can be resolved without derivatization on the pentyl cage-coated capillary column. The reproducibility of the pentyl cage-coated capillary column for separation was investigated using nitrochlorobenzene and styrene oxide as analytes. The results indicate that the column has good stability and separation reproducibility after being repeatedly used. This work demonstrates that molecular organic cage compounds could become a novel class of chiral separation media in the near future. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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2305 KiB

Open AccessArticle

Synthesis of Optically Active Poly(diphenylacetylene)s Using Polymer Reactions and an Evaluation of Their Chiral Recognition Abilities as Chiral Stationary Phases for HPLC

by Katsuhiro Maeda, Miyuki Maruta, Yuki Sakai, Tomoyuki Ikai and Shigeyoshi Kanoh

Molecules 2016, 21(11), 1487; https://doi.org/10.3390/molecules21111487 - 7 Nov 2016

Cited by 38 | Viewed by 8178

Abstract

A series of optically active poly(diphenylacetylene) derivatives bearing a chiral substituent (poly-2S) or chiral and achiral substituents (poly-(2S_x-co-3_1−x)) on all of their pendant phenyl rings were synthesized by the reaction of [...] Read more.

A series of optically active poly(diphenylacetylene) derivatives bearing a chiral substituent (poly-2S) or chiral and achiral substituents (poly-(2S_x-co-3_1−x)) on all of their pendant phenyl rings were synthesized by the reaction of poly(bis(4-carboxyphenyl)acetylene) with (S)-1-phenylethylamine ((S)-2) or benzylamine (3) in the presence of a condensing reagent. Their chiroptical properties and chiral recognition abilities as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) were investigated. Poly-2S and poly-(2S_x-co-3_1−x) (0.06 < x < 0.71) formed a preferred-handed helical conformation with opposite helical senses after thermal annealing despite possessing the same chiral pendant (h-poly-2S and h-poly-(2S_x-co-3_1−x)). Furthermore, h-poly-2S and h-poly-(2S_0.36-co-3_0.64) emitted circularly polarized luminescence with opposite signs. h-Poly-2S showed higher chiral recognition abilities toward a larger number of racemates than poly-2S without a preferred-handed helicity and the previously reported preferred-handed poly(diphenylacetylene) derivative bearing the same chiral substituent on half of its pendant phenyl rings. h-Poly-(2S_0.36-co-3_0.64) also exhibited good chiral recognition abilities toward several racemates, though the elution order of some enantiomers was reversed compared with h-poly-2S. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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9305 KiB

Open AccessArticle

Mining Chromatographic Enantioseparation Data Using Matched Molecular Pair Analysis

by Robert P. Sheridan, Patrick Piras, Edward C. Sherer, Christian Roussel, William H. Pirkle and Christopher J. Welch

Molecules 2016, 21(10), 1297; https://doi.org/10.3390/molecules21101297 - 29 Sep 2016

Cited by 7 | Viewed by 6509

Abstract

We apply matched molecular pair (MMP) analysis to data from ChirBase, which contains literature reports of chromatographic enantioseparations. For the 19 chiral stationary phases we examined, we were able to identify 289 sets of pairs where there is a statistically significant and consistent [...] Read more.

We apply matched molecular pair (MMP) analysis to data from ChirBase, which contains literature reports of chromatographic enantioseparations. For the 19 chiral stationary phases we examined, we were able to identify 289 sets of pairs where there is a statistically significant and consistent difference in enantioseparation due to a small chemical change. In many cases these changes highlight enantioselectivity differences between pairs or small families of closely related molecules that have for many years been used to probe the mechanisms of chromatographic chiral recognition; for example, the comparison of N-H vs. N-Me analytes to determine the criticality of an N-H hydrogen bond in chiral molecular recognition. In other cases, statistically significant MMPs surfaced by the analysis are less familiar or somewhat puzzling, sparking a need to generate and test hypotheses to more fully understand. Consequently, mining of appropriate datasets using MMP analysis provides an important new approach for studying and understanding the process of chromatographic enantioseparation. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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955 KiB

Open AccessArticle

Preparation of Two New Diasteromeric Chiral Stationary Phases Based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid and (R)- or (S)-1-(1-Naphthyl)ethylamine and Chiral Tethering Group Effect on the Chiral Recognition

by Rajalingam Agneeswari, Ji Yeong Sung, Eun Sol Jo, Hee Young Jeon, Vellaiappillai Tamilavan and Myung Ho Hyun

Molecules 2016, 21(8), 1051; https://doi.org/10.3390/molecules21081051 - 12 Aug 2016

Cited by 6 | Viewed by 4365

Abstract

Two new diastereomeric chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral tethering group and a Π-basic chiral unit such as (R)-1-(1-naphthyl)ethylamine (CSP 1) or (S)-1-(1-naphthyl)ethylamine (CSP 2) were prepared. The two CSPs were applied [...] Read more.

Two new diastereomeric chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral tethering group and a Π-basic chiral unit such as (R)-1-(1-naphthyl)ethylamine (CSP 1) or (S)-1-(1-naphthyl)ethylamine (CSP 2) were prepared. The two CSPs were applied to the enantiomeric separation of N-(3,5-dinitrobenzoyl)-1-phenylalkylamines and N-(3,5-dinitrobenzoyl)-α-amino acid derivatives using 20% isopropyl alcohol in hexane as a normal mobile phase. To elucidate the effect of the two chiral units on the chiral recognition, the chiral recognition abilities of the two CSPs were compared with each other and with that of a CSP (CSP 3) based on (R)-1-(1-naphthyl)ethylamine. From the chromatographic chiral recognition results, (R)-1-(1-naphthyl)ethylamine and (+)−(18-crown-6)-2,3,11,12-tetracarboxylic acid constituting CSP 1 were concluded to show a cooperative (“matched”) effect on the chiral recognition while (S)-1-(1-naphthyl)ethylamine and (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid constituting CSP 2 were concluded to show an uncooperative (“mismatched”) effect on the chiral recognition. From these results, it was concluded that (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid can be successfully used as a chiral tethering group for the preparation of new CSPs. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1425 KiB

Open AccessArticle

Aldol Reactions of Axially Chiral 5-Methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones

by Sule Erol Gunal and Ilknur Dogan

Molecules 2016, 21(6), 788; https://doi.org/10.3390/molecules21060788 - 18 Jun 2016

Cited by 1 | Viewed by 5390

Abstract

Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved [...] Read more.

Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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4057 KiB

Open AccessArticle

Nanocellulose Derivative/Silica Hybrid Core-Shell Chiral Stationary Phase: Preparation and Enantioseparation Performance

by Xiaoli Zhang, Litao Wang, Shuqing Dong, Xia Zhang, Qi Wu, Liang Zhao and Yanping Shi

Molecules 2016, 21(5), 561; https://doi.org/10.3390/molecules21050561 - 4 May 2016

Cited by 11 | Viewed by 7900

Abstract

Core-shell silica microspheres with a nanocellulose derivative in the hybrid shell were successfully prepared as a chiral stationary phase by a layer-by-layer self-assembly method. The hybrid shell assembled on the silica core was formed using a surfactant as template by the copolymerization reaction [...] Read more.

Core-shell silica microspheres with a nanocellulose derivative in the hybrid shell were successfully prepared as a chiral stationary phase by a layer-by-layer self-assembly method. The hybrid shell assembled on the silica core was formed using a surfactant as template by the copolymerization reaction of tetraethyl orthosilicate and the nanocellulose derivative bearing triethoxysilyl and 3,5-dimethylphenyl groups. The resulting nanocellulose hybrid core-shell chiral packing materials (CPMs) were characterized and packed into columns, and their enantioseparation performance was evaluated by high performance liquid chromatography. The results showed that CPMs exhibited uniform surface morphology and core-shell structures. Various types of chiral compounds were efficiently separated under normal and reversed phase mode. Moreover, chloroform and tetrahydrofuran as mobile phase additives could obviously improve the resolution during the chiral separation processes. CPMs still have good chiral separation property when eluted with solvent systems with a high content of tetrahydrofuran and chloroform, which proved the high solvent resistance of this new material. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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1375 KiB

Open AccessReview

Chromatographic Separation of Vitamin E Enantiomers

by Ju-Yen Fu, Thet-Thet Htar, Leanne De Silva, Doryn Meam-Yee Tan and Lay-Hong Chuah

Molecules 2017, 22(2), 233; https://doi.org/10.3390/molecules22020233 - 4 Feb 2017

Cited by 19 | Viewed by 7609

Abstract

Vitamin E is recognized as an essential vitamin since its discovery in 1922. Most vegetable oils contain a mixture of tocopherols and tocotrienols in the vitamin E composition. Structurally, tocopherols and tocotrienols share a similar chromanol ring and a side chain at the [...] Read more.

Vitamin E is recognized as an essential vitamin since its discovery in 1922. Most vegetable oils contain a mixture of tocopherols and tocotrienols in the vitamin E composition. Structurally, tocopherols and tocotrienols share a similar chromanol ring and a side chain at the C-2 position. Owing to the three chiral centers in tocopherols, they can appear as eight different stereoisomers. Plant sources of tocopherol are naturally occurring in the form of RRR while synthetic tocopherols are usually in the form of all-racemic mixture. Similarly, with only one chiral center, natural tocotrienols occur as the R-isoform. In this review, we aim to discuss a few chromatographic methods that had been used to separate the stereoisomers of tocopherols and tocotrienols. These methods include high performance liquid chromatography, gas chromatography and combination of both. The review will focus on method development including selection of chiral columns, detection method and choice of elution solvent in the context of separation efficiency, resolution and chiral purity. The applications for separation of enantiomers in vitamin E will also be discussed especially in terms of the distinctive biological potency among the stereoisoforms. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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9631 KiB

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The Reciprocal Principle of Selectand-Selector-Systems in Supramolecular Chromatography †

by Volker Schurig

Molecules 2016, 21(11), 1535; https://doi.org/10.3390/molecules21111535 - 15 Nov 2016

Cited by 20 | Viewed by 7008

Abstract

In selective chromatography and electromigration methods, supramolecular recognition of selectands and selectors is due to the fast and reversible formation of association complexes governed by thermodynamics. Whereas the selectand molecules to be separated are always present in the mobile phase, the selector employed [...] Read more.

In selective chromatography and electromigration methods, supramolecular recognition of selectands and selectors is due to the fast and reversible formation of association complexes governed by thermodynamics. Whereas the selectand molecules to be separated are always present in the mobile phase, the selector employed for the separation of the selectands is either part of the stationary phase or is added to the mobile phase. By the reciprocal principle, the roles of selector and selectand can be reversed. In this contribution in honor of Professor Stig Allenmark, the evolution of the reciprocal principle in chromatography is reviewed and its advantages and limitations are outlined. Various reciprocal scenarios, including library approaches, are discussed in efforts to optimize selectivity in separation science. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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12671 KiB

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HPLC Separation of Diastereomers: Chiral Molecular Tools Useful for the Preparation of Enantiopure Compounds and Simultaneous Determination of Their Absolute Configurations

by Nobuyuki Harada

Molecules 2016, 21(10), 1328; https://doi.org/10.3390/molecules21101328 - 4 Oct 2016

Cited by 17 | Viewed by 9094

Abstract

To obtain enantiopure compounds, the so-called chiral high performance liquid chromatography (HPLC) method, i.e., HPLC using a chiral stationary phase, is very useful, as reviewed in the present Special Issue. On the other hand, normal HPLC (on silica gel) separation of diastereomers is [...] Read more.

To obtain enantiopure compounds, the so-called chiral high performance liquid chromatography (HPLC) method, i.e., HPLC using a chiral stationary phase, is very useful, as reviewed in the present Special Issue. On the other hand, normal HPLC (on silica gel) separation of diastereomers is also useful for the preparation of enantiopure compounds and also for the simultaneous determination of their absolute configurations (ACs). The author and coworkers have developed some chiral molecular tools, e.g., camphorsultam dichlorophthalic acid (CSDP acid), 2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid), and others suitable for this purpose. For example, a racemic alcohol is esterified with (S)-(+)-MαNP acid, yielding diastereomeric esters, which are easily separable by HPLC on silica gel. The ACs of the obtained enantiopure MαNP esters can be determined by the ¹H-NMR diamagnetic anisotropy method. In addition, MαNP or CSDP esters have a high probability of giving single crystals suitable for X-ray crystallography. From the X-ray Oak Ridge thermal ellipsoid plot (ORTEP) drawing, the AC of the alcohol part can be unambiguously determined because the AC of the acid part is already known. The hydrolysis of MαNP or CSDP esters yields enantiopure alcohols with the established ACs. The mechanism and application examples of these methods are explained. Full article

(This article belongs to the Special Issue Chromatographic Separation of Enantiomers: Commemorative Issue in Honor of Professor Stig Allenmark on the Occasion of His 80th Birthday)

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