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Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 19937

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Special Issue Editors

Prof. Dr. Maria Elizabeth Tiritan

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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

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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 first edition of the Special Issue on "Enantioselective Synthesis, Enantiomeric Separations, and Chiral Recognition" was very rewarding comprising nineteen papers. Thus, due to the great success of this first edition, a second edition for this topic will be edited.

The importance to obtain pure enantiomers either by enantioseparation or by enantioselective synthesis 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, and preparative enantioseparation, as well as in chiral recognition studies.

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

Innovative approaches in the field of enantioselective synthesis, chiral analyses via chromatographic methods, the determination of enantiomeric purity, and chiral recognition studies are particularly welcome. Special attention will be paid to enantioseparation via membranes and supercritical fluid chromatography.

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

Manuscript Submission Information

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Keywords

Enantioseparation
Chiral chromatography
Chiral recognition
Chiral analyses
Enantioselective synthesis

Published Papers (6 papers)

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Research

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12 pages, 1827 KiB

Open AccessArticle

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

by Jie Wang and Yangfeng Peng

Molecules 2021, 26(18), 5536; https://doi.org/10.3390/molecules26185536 - 12 Sep 2021

Cited by 5 | Viewed by 1917

Abstract

The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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12 pages, 2289 KiB

Open AccessArticle

Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones and Study of Their In Vitro Metabolic Profile

by Solida Long, Izadora L. Furlani, Juliana M. de Oliveira, Diana I. S. P. Resende, Artur M. S. Silva, Luís Gales, José A. Pereira, Anake Kijjoa, Quezia B. Cass, Regina V. Oliveira, Emília Sousa and Madalena M. M. Pinto

Molecules 2021, 26(16), 5070; https://doi.org/10.3390/molecules26165070 - 21 Aug 2021

Cited by 3 | Viewed by 2595

Abstract

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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Review

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23 pages, 3759 KiB

Open AccessReview

Strategies for Preparation of Chiral Stationary Phases: Progress on Coating and Immobilization Methods

by Carla Fernandes, Joana Teixeira, Madalena M. M. Pinto and Maria Elizabeth Tiritan

Molecules 2021, 26(18), 5477; https://doi.org/10.3390/molecules26185477 - 09 Sep 2021

Cited by 9 | Viewed by 2937

Abstract

Enantioselective chromatography is one of the most used techniques for the separation and purification of enantiomers. The most important issue for a specific successful enantioseparation is the selection of the suitable chiral stationary phase (CSP). Different synthetic approaches have been applied for the preparation of CSPs, which embrace coating and immobilization methods. In addition to the classical and broadly applied coating and immobilization procedures, innovating strategies have been introduced recently. In this review, an overview of different methods for the preparation of coated and immobilized CSPs is described. Updated examples of CSPs associated with the various strategies are presented. Considering that after the preparation of a CSP its characterization is fundamental, the methods used for the characterization of all the described CSPs are emphasized. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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15 pages, 951 KiB

Open AccessReview

Enantioselectivity Effects in Clinical Metabolomics and Lipidomics

by Regina V. Oliveira, Ana Valéria C. Simionato and Quezia B. Cass

Molecules 2021, 26(17), 5231; https://doi.org/10.3390/molecules26175231 - 28 Aug 2021

Cited by 11 | Viewed by 3187

Abstract

Metabolomics and lipidomics have demonstrated increasing importance in underlying biochemical mechanisms involved in the pathogenesis of diseases to identify novel drug targets and/or biomarkers for establishing therapeutic approaches for human health. Particularly, bioactive metabolites and lipids have biological activity and have been implicated in various biological processes in physiological conditions. Thus, comprehensive metabolites, and lipids profiling are required to obtain further advances in understanding pathophysiological changes that occur in cells and tissues. Chirality is one of the most important phenomena in living organisms and has attracted long-term interest in medical and natural science. Enantioselective separation plays a pivotal role in understanding the distribution and physiological function of a diversity of chiral bioactive molecules. In this context, it has been the goal of method development for targeted and untargeted metabolomics and lipidomic assays. Herein we will highlight the benefits and challenges involved in these stereoselective analyses for clinical samples. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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40 pages, 1179 KiB

Open AccessReview

Application of Experimental Design Methodologies in the Enantioseparation of Pharmaceuticals by Capillary Electrophoresis: A Review

by Gabriel Hancu, Serena Orlandini, Lajos Attila Papp, Adriana Modroiu, Roberto Gotti and Sandra Furlanetto

Molecules 2021, 26(15), 4681; https://doi.org/10.3390/molecules26154681 - 02 Aug 2021

Cited by 20 | Viewed by 2618

Abstract

Chirality is one of the major issues in pharmaceutical research and industry. Capillary electrophoresis (CE) is an interesting alternative to the more frequently used chromatographic techniques in the enantioseparation of pharmaceuticals, and is used for the determination of enantiomeric ratio, enantiomeric purity, and in pharmacokinetic studies. Traditionally, optimization of CE methods is performed using a univariate one factor at a time (OFAT) approach; however, this strategy does not allow for the evaluation of interactions between experimental factors, which may result in ineffective method development and optimization. In the last two decades, Design of Experiments (DoE) has been frequently employed to better understand the multidimensional effects and interactions of the input factors on the output responses of analytical CE methods. DoE can be divided into two types: screening and optimization designs. Furthermore, using Quality by Design (QbD) methodology to develop CE-based enantioselective techniques is becoming increasingly popular. The review presents the current use of DoE methodologies in CE-based enantioresolution method development and provides an overview of DoE applications in the optimization and validation of CE enantioselective procedures in the last 25 years. Moreover, a critical perspective on how different DoE strategies can aid in the optimization of enantioseparation procedures is presented. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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16 pages, 2672 KiB

Open AccessFeature PaperReview

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

by Madalena M.M. Pinto, Carla Fernandes and Maria E. Tiritan

Molecules 2020, 25(8), 1931; https://doi.org/10.3390/molecules25081931 - 21 Apr 2020

Cited by 48 | Viewed by 5519

Abstract

Enantiomeric separation is a key step in the development of a new chiral drug. Preparative liquid chromatography (LC) continues to be the technique of choice either during the drug discovery process, to achieve a few milligrams, or to a scale-up during the clinical trial, needing kilograms of material. However, in the last few years, instrumental and technical developments allowed an exponential increase of preparative enantioseparation using other techniques. Besides LC, supercritical fluid chromatography (SFC) and counter-current chromatography (CCC) have aroused interest for preparative chiral separation. This overview will highlight the importance to scale-up chiral separations in Medicinal Chemistry, especially in the early stages of the pipeline of drugs discovery and development. Few examples within different methodologies will be selected, emphasizing the trends in chiral preparative separation. The advantages and drawbacks will be critically discussed. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition II)

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