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Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition
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Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 87597

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Maria Elizabeth Tiritan

E-Mail Website1 Website2
Guest Editor
1. Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
2. TOXRUN–Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
Interests: organic and pharmaceutical chemistry; chromatography; chirality; organic environmental pollutants
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Madalena Pinto

E-Mail Website1 Website2
Guest Editor
1. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2. Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
Interests: medicinal chemistry; organic synthesis; natural products; xanthones; flavonoids; antimicrobials; antitumor; antifouling
Special Issues, Collections and Topics in MDPI journals
Dr. Carla Fernandes

E-Mail Website
Guest Editor
1. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2. Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
Interests: medicinal chemistry; organic chemistry; chiral bioactive substances; enantioselective studies; chirality; chromatography
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The importance of developing analytic methods and the search for bioactive/behaviors of enantiomers is well recognized by academics and industries. Currently, the demand for efficient methodologies to obtain chiral bioactive compounds with a high degree of enantiomeric purity requires continuous advances in enantioselective synthesis, chiral analyses, preparative enantioseparation, and chiral recognition studies.

The main aims of the present Special Issue on "Enantioselective Synthesis, Enantiomeric Separations, and Chiral Recognition" include both fundamental studies and applications in a multidisciplinary research field that enrolls chiral compounds in general. Contributions to this issue, both in the form of original research or review articles, have the broad scope to illustrate recent and future trends in methodologies to obtain enantiomers in a highly enantiomeric pure form, and studies of chiral recognition in enantiomeric separations as well as in pharmacodynamic, pharmacokinetic, and toxicological events.

Innovative approaches in the field of enantioselective synthesis, chiral analyses by chromatographic methods, and the determination of enantiomeric purity and chiral recognition studies—both in enantioseparation and in biological systems—are particularly welcome.

Prof. Dr. Maria Elizabeth Tiritan
Prof. Dr. Madalena Pinto
Prof. Dr. Carla Sofia Garcia Fernandes
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enantioseparation
  • chiral chromatography
  • chiral recognition
  • chiral analyses
  • enantioselective synthesis

Published Papers (20 papers)

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Editorial

Jump to: Research, Review

5 pages, 914 KiB  
Editorial
Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition
by Maria Elizabeth Tiritan, Madalena Pinto and Carla Fernandes
Molecules 2020, 25(7), 1713; https://doi.org/10.3390/molecules25071713 - 08 Apr 2020
Cited by 8 | Viewed by 2466
Abstract
Chirality is a geometric property associated with the asymmetry of tridimensional features that accompanies our daily life at macroscopic as well as microscopic molecular levels [...] Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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Research

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11 pages, 2385 KiB  
Article
On the Enantioselective HPLC Separation Ability of Sub-2 µm Columns: Chiralpak® IG-U and ID-U
by Diana Ibrahim and Ashraf Ghanem
Molecules 2019, 24(7), 1287; https://doi.org/10.3390/molecules24071287 - 02 Apr 2019
Cited by 9 | Viewed by 3641
Abstract
Silica with a particle size of 3–5 µm has been widely used as selector backbone material in 10–25 cm HPLC chiral columns. Yet, with the availability of 1.6 µm particles, shorter, high-efficiency columns practical for minute chiral separations are possible to fabricate. Herein, [...] Read more.
Silica with a particle size of 3–5 µm has been widely used as selector backbone material in 10–25 cm HPLC chiral columns. Yet, with the availability of 1.6 µm particles, shorter, high-efficiency columns practical for minute chiral separations are possible to fabricate. Herein, we investigate the use of two recently commercialized sub-2 µm columns with different substituents. Thus, Chiralpak® IG-U and ID-U were used in HPLC for the fast enantioseparation of a set of drugs. Chiralpak® IG-U [amylose tris (3-chloro-5-methylphenylcarbamate)] has two substituents on the phenyl ring, namely, a withdrawing chlorine group in the third position and a donating group in the fifth position. Chiralpak® ID-U [amylose tris (3-chlorophenylcarbamate)] has only one substituent on the phenyl ring, namely a withdrawing chlorine group. Their applications in three liquid chromatography modes, namely, normal phase, polar organic mode, and reversed phase, were demonstrated. Both columns have similar column parameters (50 mm length, 3 mm internal diameter, and 1.6 µm particle size) with the chiral stationary phase as the only variable. Improved chromatographic enantioresolution was obtained with Chiralpak® ID-U. Amino acids partially separated were reported for the first time under an amylose-based sub-2-micron column. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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11 pages, 1390 KiB  
Article
Determination of Optical Purity of Lactic Acid-Based Chiral Liquid Crystals and Corresponding Building Blocks by Chiral High-Performance Liquid Chromatography and Supercritical Fluid Chromatography
by Anna Poryvai, Terezia Vojtylová-Jurkovičová, Michal Šmahel, Natalie Kolderová, Petra Tomášková, David Sýkora and Michal Kohout
Molecules 2019, 24(6), 1099; https://doi.org/10.3390/molecules24061099 - 20 Mar 2019
Cited by 19 | Viewed by 3220
Abstract
Liquid crystals (LCs) are among the most prominent materials of the current information age, mainly due to their well-known application in liquid crystal displays (LCDs). Their unique electro-optical properties stem from their ability to form organised structures (mesophases) on the transition from solid [...] Read more.
Liquid crystals (LCs) are among the most prominent materials of the current information age, mainly due to their well-known application in liquid crystal displays (LCDs). Their unique electro-optical properties stem from their ability to form organised structures (mesophases) on the transition from solid state to isotropic liquid. Molecules of LCs in a mesophase still maintain the anisotropy of solid crystals, while simultaneously exhibiting the fluidity of liquids, which gives the system the ability to react immediately to external stimuli such as electric or magnetic fields, light, mechanical stress, pressure and, of course, temperature. For the proper function of LC-based devices, not only chemical, but also optical purity of materials is strongly desirable, since any impurity could be detrimental to the self-assembly of the molecules. Therefore, in this study we aimed to verify synthetic methods published in the literature, which are used nowadays to prepare chiral building blocks based on lactic acid, for their enantioselectivity. Moreover, we have focused on the development of an analytical chiral separation method for target liquid crystalline materials. Using a chiral polysaccharide-based column operated in liquid chromatography mode, we show that not all published methods of LC synthesis are enantioselective, which could lead to significant differences in the properties of the resulting materials. We show that high-performance liquid chromatography with UV detection and supercritical fluid chromatography with UV and mass spectrometry detection enable full control over the chemical and optical purity of the target LCs and the corresponding chiral building blocks. For the first time, we utilise supercritical fluid chromatography with mass detection for the direct chiral analysis of liquid crystalline materials and impurities formed during the synthesis. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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10 pages, 1446 KiB  
Article
Hemi-Synthesis of Chiral Imine, Benzimidazole and Benzodiazepines from Essential Oil of Ammodaucus leucotrichus subsp. leucotrichus
by Farid Chebrouk, Khodir Madani, Brahim Cherfaoui, Leila Boukenna, Mónica Válega, Ricardo F. Mendes, Filipe A. A. Paz, Khaldoun Bachari, Oualid Talhi and Artur M. S. Silva
Molecules 2019, 24(5), 975; https://doi.org/10.3390/molecules24050975 - 10 Mar 2019
Cited by 10 | Viewed by 4077
Abstract
The hemi-synthesis of chiral imine, benzimidazole and benzodiazepine structures is reported by the condensation of (S)-(−)-perillaldehyde, the major phytochemical of Ammodaucus leucotrichus subsp. leucotrichus essential oil, with different amine derivatives of 2,3-diaminomaleonitrile, o-phenylenediamine and 3-[(2-aminoaryl)amino]dimedone. The reaction proceeds in situ [...] Read more.
The hemi-synthesis of chiral imine, benzimidazole and benzodiazepine structures is reported by the condensation of (S)-(−)-perillaldehyde, the major phytochemical of Ammodaucus leucotrichus subsp. leucotrichus essential oil, with different amine derivatives of 2,3-diaminomaleonitrile, o-phenylenediamine and 3-[(2-aminoaryl)amino]dimedone. The reaction proceeds in situ at ambient temperature without prior isolation of the natural (S)-(−)-perillaldehyde. Final products precipitate in the ethanolic reaction medium. 2D NMR and single-crystal X-ray diffraction studies were used to unequivocally characterize the structures in solution and in the solid state, respectively. Chiral HPLC analysis confirms the formation of unique enantiomers and diastereomeric mixtures. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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10 pages, 3029 KiB  
Article
Enhanced Near-Field Chirality in Periodic Arrays of Si Nanowires for Chiral Sensing
by Emilija Petronijevic and Concita Sibilia
Molecules 2019, 24(5), 853; https://doi.org/10.3390/molecules24050853 - 28 Feb 2019
Cited by 12 | Viewed by 2977
Abstract
Nanomaterials can be specially designed to enhance optical chirality and their interaction with chiral molecules can lead to enhanced enantioselectivity. Here we propose periodic arrays of Si nanowires for the generation of enhanced near-field chirality. Such structures confine the incident electromagnetic field into [...] Read more.
Nanomaterials can be specially designed to enhance optical chirality and their interaction with chiral molecules can lead to enhanced enantioselectivity. Here we propose periodic arrays of Si nanowires for the generation of enhanced near-field chirality. Such structures confine the incident electromagnetic field into specific resonant modes, which leads to an increase in local optical chirality. We investigate and optimize near-field chirality with respect to the geometric parameters and excitation scheme. Specially, we propose a simple experiment for the enhanced enantioselectivity, and optimize the average chirality depending on the possible position of the chiral molecule. We believe that such a simple achiral nanowire approach can be functionalized to give enhanced chirality in the spectral range of interest and thus lead to better discrimination of enantiomers. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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15 pages, 3762 KiB  
Article
Colistin Sulfate Chiral Stationary Phase for the Enantioselective Separation of Pharmaceuticals Using Organic Polymer Monolithic Capillary Chromatography
by Ali Fouad, Montaser Sh. A. Shaykoon, Samy M. Ibrahim, Sobhy M. El-Adl and Ashraf Ghanem
Molecules 2019, 24(5), 833; https://doi.org/10.3390/molecules24050833 - 26 Feb 2019
Cited by 16 | Viewed by 4408
Abstract
A new functionalized polymer monolithic capillary with a macrocyclic antibiotic, namely colistin sulfate, as chiral selector was prepared via the copolymerization of binary monomer mixtures consisting of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in porogenic solvents namely 1-propanol and 1,4-butanediol, in [...] Read more.
A new functionalized polymer monolithic capillary with a macrocyclic antibiotic, namely colistin sulfate, as chiral selector was prepared via the copolymerization of binary monomer mixtures consisting of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in porogenic solvents namely 1-propanol and 1,4-butanediol, in the presence of azobisiso-butyronitrile (AIBN) as initiator and colistin sulfate. The prepared capillaries were investigated for the enantioselective nano-LC separation of a group of racemic pharmaceuticals, namely, α- and β-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Acceptable separation was achieved for many drugs using reversed phase chromatographic conditions with no separation achieved under normal phase conditions. Colistin sulfate appears to be useful addition to the available macrocyclic antibiotic chiral phases used in liquid chromatography. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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16 pages, 2773 KiB  
Article
New Brush-Type Chiral Stationary Phases for Enantioseparation of Pharmaceutical Drugs
by Anamarija Knežević, Jurica Novak and Vladimir Vinković
Molecules 2019, 24(4), 823; https://doi.org/10.3390/molecules24040823 - 25 Feb 2019
Cited by 7 | Viewed by 4346
Abstract
The importance of chirality in drug development is unquestionable, with chiral liquid chromatography (LC) being the most adequate technique for its analysis. Among the various types of chiral stationary phases (CSPs) for LC, brush-type CSPs provide the base for interaction analysis of CSPs [...] Read more.
The importance of chirality in drug development is unquestionable, with chiral liquid chromatography (LC) being the most adequate technique for its analysis. Among the various types of chiral stationary phases (CSPs) for LC, brush-type CSPs provide the base for interaction analysis of CSPs and enantiomers, which provide valuable results that can be applied to interaction studies of other CSP types. In order to analyze the influence of aromatic interactions in chiral recognition, we designed a set of ten new brush-type CSPs based on (S)-N-(1-aryl-propyl)-3,5-dinitrobenzamides which differ in the aromatic unit directly linked to the chiral center. Thirty diverse racemates, including several nonsteroidal anti-inflammatory drugs and 3-hydroxybenzodiazepine drugs, were used to evaluate the prepared CSPs. Chromatographic analysis showed that the three new CSPs separate enantiomers of a wide range of compounds and their chromatographic behavior is comparable to the most versatile brush-type CSP—Whelk-O1. The critical role of the nonbonding interactions in positioning of the analyte (naproxen) in the cleft of CSP-6, as well as the analysis of interactions that make enantioseparation possible, were elucidated using computational methods. Furthermore, the influence of acetic acid as a mobile phase additive, on this enantiorecognition process was corroborated by calculations. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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17 pages, 2634 KiB  
Article
Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects
by Solida Long, Diana I. S. P. Resende, Anake Kijjoa, Artur M. S. Silva, Ricardo Fernandes, Cristina P. R. Xavier, M. Helena Vasconcelos, Emília Sousa and Madalena M. M. Pinto
Molecules 2019, 24(3), 534; https://doi.org/10.3390/molecules24030534 - 01 Feb 2019
Cited by 21 | Viewed by 4267
Abstract
New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs [...] Read more.
New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs by the Mazurkiewicz-Ganesan approach. The neuroprotection capacity of these compounds on the rotenone-damage human neuroblastoma cell SH-SY5y was evaluated using the MTT assay. Compounds 1, 3, 5, and 7 showed more than 25% protection. The antitumor activity was investigated using the sulforhodamine B assay and some compounds were tested on the non-malignant MCF-12A cells. Fumiquinazoline G (1) was the most potent compound, with GI50 values lower than 20 µM. Compounds 5, 7, and 11 were more active in all tumor cell lines when compared to their enantiomers. Compounds 5, 7, 10, and 11 had very little effect in the viability of the non-malignant cells. Differences between enantiomeric pairs were also noted as being essential for these activities the S-configuration at C-4. These results reinforce the previously described activities of the fiscalin B (3) as substance P inhibitor and fumiquinazoline G (1) as antitumor agent showing potential as lead compounds for the development of drugs for treatment of neurodegenerative disorders and cancer, respectively. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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9 pages, 2963 KiB  
Article
An Enantioselective Potentiometric Sensor for 2-Amino-1-Butanol Based on Chiral Porous Organic Cage CC3-R
by Bang-Jin Wang, Ai-Hong Duan, Jun-Hui Zhang, Sheng-Ming Xie, Qiu-E Cao and Li-Ming Yuan
Molecules 2019, 24(3), 420; https://doi.org/10.3390/molecules24030420 - 24 Jan 2019
Cited by 9 | Viewed by 3837
Abstract
Porous organic cages (POCs) have attracted extensive attention due to their unique structures and tremendous application potential in numerous areas. In this study, an enantioselective potentiometric sensor composed of a polyvinyl chloride (PVC) membrane electrode modified with CC3-R POC material was used for [...] Read more.
Porous organic cages (POCs) have attracted extensive attention due to their unique structures and tremendous application potential in numerous areas. In this study, an enantioselective potentiometric sensor composed of a polyvinyl chloride (PVC) membrane electrode modified with CC3-R POC material was used for the recognition of enantiomers of 2-amino-1-butanol. After optimisation, the developed sensor exhibited enantioselectivity toward S-2-amino-1-butanol ( log K S , R P o t = −0.98) with acceptable sensitivity, and a near-Nernstian response of 25.8 ± 0.3 mV/decade within a pH range of 6.0–9.0. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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12 pages, 2884 KiB  
Article
Probing the Structural Determinants of Amino Acid Recognition: X-Ray Studies of Crystalline Ditopic Host-Guest Complexes of the Positively Charged Amino Acids, Arg, Lys, and His with a Cavitand Molecule
by Giovanna Brancatelli, Enrico Dalcanale, Roberta Pinalli and Silvano Geremia
Molecules 2018, 23(12), 3368; https://doi.org/10.3390/molecules23123368 - 19 Dec 2018
Cited by 7 | Viewed by 3600
Abstract
Crystallization of tetraphosphonate cavitand Tiiii[H, CH3, CH3] in the presence of positively charged amino acids, namely arginine, lysine, or histidine, afforded host-guest complex structures. The X-ray structure determination revealed that in all three structures, the fully protonated form of [...] Read more.
Crystallization of tetraphosphonate cavitand Tiiii[H, CH3, CH3] in the presence of positively charged amino acids, namely arginine, lysine, or histidine, afforded host-guest complex structures. The X-ray structure determination revealed that in all three structures, the fully protonated form of the amino acid is ditopically complexed by two tetraphosphonate cavitand molecules. Guanidinium, ammonium, and imidazolium cationic groups of the amino acid side chain are hosted in the cavity of a phosphonate receptor, and are held in place by specific hydrogen bonding interactions with the P=O groups of the cavitand molecule. In all three structures, the positively charged α-ammonium groups form H-bonds with the P=O groups, and with a water molecule hosted in the cavity of a second tetraphosphonate molecule. Furthermore, water-assisted dimerization was observed for the cavitand/histidine ditopic complex. In this 4:2 supramolecular complex, a bridged water molecule is held by two carboxylic acid groups of the dimerized amino acid. The structural information obtained on the geometrical constrains necessary for the possible encapsulation of the amino acids are important for the rational design of devices for analytical and medical applications. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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12 pages, 881 KiB  
Article
Improved Resolution of 4-Chloromandelic Acid and the Effect of Chlorine Interactions Using (R)-(+)-Benzyl-1-Phenylethylamine as a Resolving Agent
by Yangfeng Peng, Cai Feng, Sohrab Rohani and Quan He
Molecules 2018, 23(12), 3354; https://doi.org/10.3390/molecules23123354 - 18 Dec 2018
Cited by 2 | Viewed by 3122
Abstract
In order to avoid the disadvantage of commonly used resolving agent 1-phenylethylamine (hereafter: PEA), which is soluble in water, (R)-(+)-benzyl-1-phenylethylamine ((R)-(+)-BPA) was used to resolve 4-chloromandelic acid (4-ClMA) in this study. The optimal resolution conditions were determined: absolute ethanol [...] Read more.
In order to avoid the disadvantage of commonly used resolving agent 1-phenylethylamine (hereafter: PEA), which is soluble in water, (R)-(+)-benzyl-1-phenylethylamine ((R)-(+)-BPA) was used to resolve 4-chloromandelic acid (4-ClMA) in this study. The optimal resolution conditions were determined: absolute ethanol as a solvent, the molar ratio of 4-ClMA to (R)-(+)-BPA as 1:1, the filtration temperature as 15 °C, and the amount of solvent as 1.6 mL/1 mmol 4-ClMA. Thermophysical properties, such as melting point, heat of fusion, and solubility, exhibited significant differences between the less and more soluble salts. The single crystals for the pair of diastereomeric salts were cultivated and their crystal structures were examined thoroughly. In addition to commonly observed interactions like hydrogen bonding and CH/π interactions. The chlorine…chlorine interaction was observed in the less soluble salt presenting as Cl…Cl between adjacent hydrogen network columns, while the Cl/π interaction was observed in the more soluble salt. It was found that halogen interactions played an important role in chiral recognition of 4-ClMA by (R)-(+)-BPA. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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11 pages, 1044 KiB  
Article
Chiral Separation of the Phenylglycinol Enantiomers by Stripping Crystallization
by Lie-Ding Shiau
Molecules 2018, 23(11), 2901; https://doi.org/10.3390/molecules23112901 - 07 Nov 2018
Cited by 3 | Viewed by 2335
Abstract
Stripping crystallization (SC) is introduced in this work for chiral purification of R-phenylglycinol from the enantiomer mixture with an initial concentration ranging from 0.90 to 0.97. As opposed to the solid–liquid transformation in melt crystallization, the three-phase transformation occurs in SC at [...] Read more.
Stripping crystallization (SC) is introduced in this work for chiral purification of R-phenylglycinol from the enantiomer mixture with an initial concentration ranging from 0.90 to 0.97. As opposed to the solid–liquid transformation in melt crystallization, the three-phase transformation occurs in SC at low pressures during the cooling process. SC combines melt crystallization and vaporization to produce a crystalline product and mixture vapor from a mixture melt due to the three-phase transformation. Thermodynamic calculations were applied to determine the operating pressure for the three-phase transformation during the cooling process in the SC experiments. To consider the possible deviations between the calculated and the actual three-phase transformation conditions, the product purity and the recovery ratio of R-phenylglycinol were investigated within a range of operating pressures during the cooling process. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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12 pages, 1628 KiB  
Article
Enantioseparation, Stereochemical Assignment and Chiral Recognition Mechanism of Sulfoxide-Containing Drugs
by Fei Xiong, Bei-Bei Yang, Jie Zhang and Li Li
Molecules 2018, 23(10), 2680; https://doi.org/10.3390/molecules23102680 - 18 Oct 2018
Cited by 14 | Viewed by 3996
Abstract
The distinct pharmacodynamic and pharmacokinetic properties of enantiopure sulfoxide drugs have stimulated us to systematically investigate their chiral separation, stereochemical assignment, and chiral recognition mechanism. Herein, four clinically widely-used sulfoxide drugs were chosen and optically resolved on various chiral stationary phases (CSPs). Theoretical [...] Read more.
The distinct pharmacodynamic and pharmacokinetic properties of enantiopure sulfoxide drugs have stimulated us to systematically investigate their chiral separation, stereochemical assignment, and chiral recognition mechanism. Herein, four clinically widely-used sulfoxide drugs were chosen and optically resolved on various chiral stationary phases (CSPs). Theoretical simulations including electronic circular dichroism (ECD) calculation and molecular docking were adopted to assign the stereochemistry and reveal the underlying chiral recognition mechanism. Our results showed that the sequence of calculated mean binding energies between each pair of enantiomers and CSP matched exactly with experimentally observed enantiomeric elution order (EEO). It was also found that the length of hydrogen bond might contribute dominantly the interaction between two enantiomers and CSP. We hope our study could provide a fresh perspective to explore the stereochemistry and chiral recognition mechanism of chiral drugs. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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20 pages, 2643 KiB  
Article
Improved Enantioselectivity for Atenolol Employing Pivot Based Molecular Imprinting
by Andreea Elena Bodoki, Bogdan-Cezar Iacob, Laura Elena Gliga, Simona Luminita Oprean, David A. Spivak, Nicholas A. Gariano and Ede Bodoki
Molecules 2018, 23(8), 1875; https://doi.org/10.3390/molecules23081875 - 27 Jul 2018
Cited by 15 | Viewed by 3932
Abstract
In the last few decades, molecular imprinting technology went through a spectacular evolution becoming a well-established tool for the synthesis of highly selective biomimetic molecular recognition platforms. Nevertheless, there is still room for advancement in the molecular imprinting of highly polar chiral compounds. [...] Read more.
In the last few decades, molecular imprinting technology went through a spectacular evolution becoming a well-established tool for the synthesis of highly selective biomimetic molecular recognition platforms. Nevertheless, there is still room for advancement in the molecular imprinting of highly polar chiral compounds. The aim of the present work was to investigate the favorable kosmotropic effect of a ternary complex involving a polar chiral template (eutomer of atenolol) and a functional monomer, bridged by a central metal ion through well-defined, spatially directional coordinate bonds. The efficiency of the chiral molecular recognition was systematically assessed on polymers obtained both by non-covalent and metal-mediated molecular imprinting. The influence on the chromatographic retention and enantioselectivity of different experimental variables (functional monomers, cross-linkers, chaotropic agents, metal ions, porogenic systems, etc.) were studied on both slurry packed and monolithic HPLC columns. Deliberate changes in the imprinting and rebinding (chromatographic) processes, along with additional thermodynamic studies shed light on the particularities of the molecular recognition mechanism. The best performing polymer in terms of enantioselectivity (α = 1.60) was achieved using 4-vinyl pyridine as functional monomer and secondary ligand for the Co(II)-mediated imprinting of S-atenolol in the presence of EDMA as cross-linker in a porogenic mixture of [BMIM][BF4]:DMF:DMSO = 10:1:5, v/v/v. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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Review

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31 pages, 3171 KiB  
Review
Enantiomeric Recognition and Separation by Chiral Nanoparticles
by Ankur Gogoi, Nirmal Mazumder, Surajit Konwer, Harsh Ranawat, Nai-Tzu Chen and Guan-Yu Zhuo
Molecules 2019, 24(6), 1007; https://doi.org/10.3390/molecules24061007 - 13 Mar 2019
Cited by 69 | Viewed by 7499
Abstract
Chiral molecules are stereoselective with regard to specific biological functions. Enantiomers differ considerably in their physiological reactions with the human body. Safeguarding the quality and safety of drugs requires an efficient analytical platform by which to selectively probe chiral compounds to ensure the [...] Read more.
Chiral molecules are stereoselective with regard to specific biological functions. Enantiomers differ considerably in their physiological reactions with the human body. Safeguarding the quality and safety of drugs requires an efficient analytical platform by which to selectively probe chiral compounds to ensure the extraction of single enantiomers. Asymmetric synthesis is a mature approach to the production of single enantiomers; however, it is poorly suited to mass production and allows for only specific enantioselective reactions. Furthermore, it is too expensive and time-consuming for the evaluation of therapeutic drugs in the early stages of development. These limitations have prompted the development of surface-modified nanoparticles using amino acids, chiral organic ligands, or functional groups as chiral selectors applicable to a racemic mixture of chiral molecules. The fact that these combinations can be optimized in terms of sensitivity, specificity, and enantioselectivity makes them ideal for enantiomeric recognition and separation. In chiral resolution, molecules bond selectively to particle surfaces according to homochiral interactions, whereupon an enantiopure compound is extracted from the solution through a simple filtration process. In this review article, we discuss the fabrication of chiral nanoparticles and look at the ways their distinctive surface properties have been adopted in enantiomeric recognition and separation. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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11 pages, 827 KiB  
Review
Enantiomeric Tartaric Acid Production Using cis-Epoxysuccinate Hydrolase: History and Perspectives
by Jinsong Xuan and Yingang Feng
Molecules 2019, 24(5), 903; https://doi.org/10.3390/molecules24050903 - 05 Mar 2019
Cited by 16 | Viewed by 5518
Abstract
Tartaric acid is an important chiral chemical building block with broad industrial and scientific applications. The enantioselective synthesis of l(+)- and d(−)-tartaric acids has been successfully achieved using bacteria presenting cis-epoxysuccinate hydrolase (CESH) activity, while the catalytic mechanisms of CESHs [...] Read more.
Tartaric acid is an important chiral chemical building block with broad industrial and scientific applications. The enantioselective synthesis of l(+)- and d(−)-tartaric acids has been successfully achieved using bacteria presenting cis-epoxysuccinate hydrolase (CESH) activity, while the catalytic mechanisms of CESHs were not elucidated clearly until very recently. As biocatalysts, CESHs are unique epoxide hydrolases because their substrate is a small, mirror-symmetric, highly hydrophilic molecule, and their products show very high enantiomeric purity with nearly 100% enantiomeric excess. In this paper, we review over forty years of the history, process and mechanism studies of CESHs as well as our perspective on the future research and applications of CESH in enantiomeric tartaric acid production. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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38 pages, 1992 KiB  
Review
Chiral Stationary Phases for Liquid Chromatography: Recent Developments
by Joana Teixeira, Maria Elizabeth Tiritan, Madalena M. M. Pinto and Carla Fernandes
Molecules 2019, 24(5), 865; https://doi.org/10.3390/molecules24050865 - 28 Feb 2019
Cited by 107 | Viewed by 8229
Abstract
The planning and development of new chiral stationary phases (CSPs) for liquid chromatography (LC) are considered as continuous and evolutionary issues since the introduction of the first CSP in 1938. The main objectives of the development strategies were to attempt the improvement of [...] Read more.
The planning and development of new chiral stationary phases (CSPs) for liquid chromatography (LC) are considered as continuous and evolutionary issues since the introduction of the first CSP in 1938. The main objectives of the development strategies were to attempt the improvement of the chromatographic enantioresolution performance of the CSPs as well as enlarge their versatility and range of applications. Additionally, the transition to ultra-high-performance LC were underscored. The most recent strategies have comprised the introduction of new chiral selectors, the use of new materials as chromatographic supports or the reduction of its particle size, and the application of different synthetic approaches for preparation of CSPs. This review gathered the most recent developments associated to the different types of CSPs providing an overview of the relevant advances that are arising on LC. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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36 pages, 8339 KiB  
Review
Synthetic Chiral Derivatives of Xanthones: Biological Activities and Enantioselectivity Studies
by Carla Fernandes, Maria Letícia Carraro, João Ribeiro, Joana Araújo, Maria Elizabeth Tiritan and Madalena M. M. Pinto
Molecules 2019, 24(4), 791; https://doi.org/10.3390/molecules24040791 - 22 Feb 2019
Cited by 33 | Viewed by 4973
Abstract
Many naturally occurring xanthones are chiral and present a wide range of biological and pharmacological activities. Some of them have been exhaustively studied and subsequently, obtained by synthesis. In order to obtain libraries of compounds for structure activity relationship (SAR) studies as well [...] Read more.
Many naturally occurring xanthones are chiral and present a wide range of biological and pharmacological activities. Some of them have been exhaustively studied and subsequently, obtained by synthesis. In order to obtain libraries of compounds for structure activity relationship (SAR) studies as well as to improve the biological activity, new bioactive analogues and derivatives inspired in natural prototypes were synthetized. Bioactive natural xanthones compromise a large structural multiplicity of compounds, including a diversity of chiral derivatives. Thus, recently an exponential interest in synthetic chiral derivatives of xanthones (CDXs) has been witnessed. The synthetic methodologies can afford structures that otherwise could not be reached within the natural products for biological activity and SAR studies. Another reason that justifies this trend is that both enantiomers can be obtained by using appropriate synthetic pathways, allowing the possibility to perform enantioselectivity studies. In this work, a literature review of synthetic CDXs is presented. The structures, the approaches used for their synthesis and the biological activities are described, emphasizing the enantioselectivity studies. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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23 pages, 4988 KiB  
Review
Stereoselective Multicomponent Reactions in the Synthesis or Transformations of Epoxides and Aziridines
by Allan Ribeiro da Silva, Deborah Araujo dos Santos, Marcio Weber Paixão and Arlene Gonçalves Corrêa
Molecules 2019, 24(3), 630; https://doi.org/10.3390/molecules24030630 - 11 Feb 2019
Cited by 21 | Viewed by 6295
Abstract
Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with [...] Read more.
Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with the advantages of environmentally benign synthetic procedures, multicomponent reactions (MCRs) have been explored in the synthesis and ring opening of these heterocyclic units. In this review, the recent advances in MCRs involving the synthesis and applications of epoxides and aziridines to the preparation of other heterocycles are discussed emphasizing the stereoselectivity of the reactions. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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13 pages, 1554 KiB  
Review
Enantioselective Drug Recognition by Drug Transporters
by Yuichi Uwai
Molecules 2018, 23(12), 3062; https://doi.org/10.3390/molecules23123062 - 22 Nov 2018
Cited by 12 | Viewed by 3550
Abstract
Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters [...] Read more.
Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review. Full article
(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition)
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