DOCSLIB.ORG

Enantiomeric Resolution and Absolute Configuration of a Chiral Δ-Lactam

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enantiomeric Resolution and Absolute Configuration of a Chiral Δ-Lactam molecules Article Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds 1, 1, 1 1 Roberta Listro y, Giacomo Rossino y, Serena Della Volpe , Rita Stabile , Massimo Boiocchi 2 , Lorenzo Malavasi 3, Daniela Rossi 1,* and Simona Collina 1 1 Department of Drug Sciences, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] (R.L.); [email protected] (G.R.); [email protected] (S.D.V.); [email protected] (R.S.); [email protected] (S.C.) 2 Centro Grandi Strumenti, University of Pavia, via Bassi 21, 27100 Pavia, Italy; [email protected] 3 Department of Chemistry, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Academic Editor: Józef Drabowicz Received: 2 December 2020; Accepted: 18 December 2020; Published: 19 December 2020 Abstract: During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams. Keywords: lactam scaffold; enantioselective HPLC; chiral resolution; X-ray diffraction; absolute configuration assignment 1. Introduction Drug discovery is a complex process aimed at identifying new biologically active compounds with a high degree of structural novelty [1]. It can be driven by the exploration of the chemical space around a drug or a selected scaffold, the core structure of the molecular framework. Scaffolds are used as starting points for compound synthesis or diversification and, therefore, their study represents an effective and promising approach for finding new potent drugs [2–5]. In recent years, substituted lactams have emerged as an important pharmacophore for several drug classes, with a large spectrum of biological outcomes and various therapeutic applications [6–8]. From a structural standpoint, they can be four-, five-, six- and seven-membered rings, called β-lactams, γ-lactam, δ-lactam and "-lactam, respectively. Several drugs with a lactam structure have already reached the market, and a few representative examples are reported in Figure1. These include antibiotics with a β-lactam structure (i.e., penicillins, cephalosporins, monobactams, carbapenems) [9], the γ-lactam Lenalidomide (a derivative of Thalidomide endowed with immunomodulatory and antiangiogenic activity) [10,11], the δ-lactam Dolutegravir (a HIV-1 integrase inhibitor) [12] and benzodiazepines based on the "-lactam scaffold (i.e., Prazepam), well known allosteric modulators of the receptor GABA A. [13]. Molecules 2020, 25, 6023; doi:10.3390/molecules25246023 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 16 immunomodulatory and antiangiogenic activity) [10,11], the δ-lactam Dolutegravir (a HIV-1 integrase inhibitor) [12] and benzodiazepines based on the ε-lactam scaffold (i.e., Prazepam), well known allosteric modulators of the receptor GABA A. [13]. Molecules 2020, 25, x 2 of 16 immunomodulatory and antiangiogenic activity) [10,11], the δ-lactam Dolutegravir (a HIV-1 integrase Moleculesinhibitor)2020 [12], 25, 6023 and benzodiazepines based on the ε-lactam scaffold (i.e., Prazepam), well known2 of 15 allosteric modulators of the receptor GABA A. [13]. Figure 1. Examples of marketed drugs based on the lactam scaffold. In the last few years, the interest of MedChem researchers towards lactams as chemical scaffolds has grown, as evidenced by the increasing number of publications (Figure 2), due to their high potential for discovering drug candidates. In fact, lactams possess attractive features such as versatility and easy derivatization, and, additionally, they are conformationally restricted scaffolds with peptidomimetic features. Thus, they can be used to improve the potency, selectivity, and metabolic stability of peptide-based drugs [7]. Several MedChem groups have focused on the synthesis of new molecular entities based on γ- or δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [14–18]. For instance, Delong et al. studied novel α-methylene-FigureFigure 1. 1.γExamples Examples-lactams, of ofα marketed-arylidene-marketed drugsdrugsγ and based ba δsed-lactams, on on the the lactam lactamwith novel sca scaffold.ffold. antifungal properties against Colletotrichum orbiculare [19], whereas Davoren et al. prepared a series of molecules with lactamInIn thescaffolds the last last few few and years, years, identified thethe interestinterest a number ofof MedChemMedChem of γ- and researchersresearchers δ-lactams towards abletowards to function lactams lactams as as chemicalpositivechemical allosteric sca scaffoldsffolds hasmodulatorshas grown, grown, as (PAMs)as evidenced evidenced of muscarinic by theby increasingthe increasingreceptors number (M1)number of [20]. publications of Lastly, publications by (Figure applying 2(Figure), due a to combined2), their due high to moleculartheir potential high formodellingpotential discovering -forSTD discovering drug NMR candidates. approach, drug In ourcandidates. fact, group lactams recently In possess fact identified, lactams attractive apossess featurespromising attractive such ligand as versatility featureswith a δ and -lactamsuch easy as derivatization,scaffoldversatility able and to and, easybind additionally, derivatization,the RNA-binding they and, are protein additionally, conformationally HuR [21–23], they restrictedare which conformationally scainteractsffolds withwith restricted peptidomimetictarget mRNAs,scaffolds features.leadingwith peptidomimetic to Thus, the formation they canfeatures. beof usedHuR–mRNA Thus, to improvethey cancomple the be potency,usedxes involvedto selectivity,improve in theseveral and potency, metabolic physio-pathological selectivity, stability and of peptide-basedconditionsmetabolic [24–26].stability drugs of [ 7peptide-based]. drugs [7]. Several MedChem groups have focused on the synthesis of new molecular entities based on γ- or δ-lactam scaffolds as highly versatile key intermediates, leading to the discovery of new 25 anti-trypanosomal, anti-biofilm and anti-inflammation agents [14–18]. For instance, Delong et al. studied novel α-methylene-20 γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare [19], whereas Davoren et al. prepared a series of molecules with lactam scaffolds and15 identified a number of γ- and δ-lactams able to function as positive allosteric modulators (PAMs)10 of muscarinic receptors (M1) [20]. Lastly, by applying a combined molecular modelling-STD NMR approach, our group recently identified a promising ligand with a δ-lactam 5 scaffold able to bind Number publications of the RNA-binding protein HuR [21–23], which interacts with target mRNAs, leading to the formation0 of HuR–mRNA complexes involved in several physio-pathological conditions [24–26]. 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 Years 25 Figure 2. Papers published20 per year. Source Scopus (31 October 2020), key words “lactams” and “medicinal chemistry”. 15 Several MedChem groups have focused on the synthesis of new molecular entities based on γ- or δ-lactam scaffolds10 as highly versatile key intermediates, leading to the discovery of new anti-trypanosomal, anti-biofilm and anti-inflammation agents [14–18]. For instance, Delong et al. 5 studied novel α-methylene- Number publications of γ-lactams, α-arylidene-γ and δ-lactams, with novel antifungal properties against Colletotrichum orbiculare0 [19], whereas Davoren et al. prepared a series of molecules with lactam scaffolds and identified a2000 number 2002 of 2004γ- and 2006δ-lactams 2008 2010 able 2012to function 2014 2016 as positive 2018 2020 allosteric modulators (PAMs) of muscarinic receptors (M1) [20]. Lastly, byYears applying a combined molecular modelling-STD NMR approach, our group recently identified a promising ligand with a δ-lactam scaffold able to bind the RNA-binding protein HuR [21–23], which interacts with target mRNAs, leading to the formation of HuR–mRNA complexes involved in several physio-pathological conditions [24–26]. Molecules 2020, 25, x 3 of 16 MoleculesFigure2020 ,2.25 Papers, 6023 published per year. Source Scopus (31 October 2020), key words “lactams” and3 of 15 “medicinal chemistry”. Given the high interest in la lactams,ctams, extensive eeffortsfforts have been directed towards the identification identification of versatile syntheticsynthetic strategies strategies for for obtaining obtaining lactams. lactams. Among Among the the di differentfferent methodologies methodologies exploited exploited so far,so far, it is it worth is worth mentioning mentioning the Beckmann the Beckmann rearrangement, rearrangement, the Staudinger the Staudinger procedure procedure
Load more

Recommended publications
  • Chiral Resolution Screening and Purification Kits Brochure
    Maybridge Chiral Resolution Screening and Purification Kits Offering rapid access to optically pure chiral compounds Maybridge Chiral Resolution Screening and Purification Kits Introduction Diastereomeric crystallization is a commonly used effective process to obtain optically pure chiral compounds from their racemic mixtures. However, choosing the optimal conditions for the process; e.g., combination of resolving agents and solvents, is time-consuming, tedious and labor-intensive. Maybridge Chiral Resolution Screening and Purification kits provide scientists with a quick and systematic approach to find the best separation conditions under which the target compound can be isolated with the highest yield and optical purity. Key features and benefits • Rapid Screening – the kits include 384 different combinations of resolving agents and solvents, increasing the chances of finding the optimal separation conditions • High Performance – development time reduced to one day • Efficient – as little as 0.4mmol of racemate required • Ready to Use – resolving agents and solvents are pre-dispensed in 96-well plates • Convenient – the screening kits provide positive results identifiable by a quick visual or optical inspection, and the purification and recovery kit allows easy recovery and purification of the enantiomers Types of Chiral Resolution Screening and Purification Kits Amount Plate Product name Description Selection guide racemate Product code type required Maybridge Chiral • 4 x 96 plates containing 32 different acidic Identifies optimal
    [Show full text]
  • II. Stereochemistry 5
    B.Sc.(H) Chemistry Semester - II Core Course - III (CC-III) Organic Chemistry - I II. Stereochemistry 5. Physical and Chemical Properties of Stereoisomers Dr. Rajeev Ranjan University Department of Chemistry Dr. Shyama Prasad Mukherjee University, Ranchi 1 Syllabus & Coverage Syllabus II Stereochemistry: Fischer Projection, Newmann and Sawhorse Projection formulae and their interconversions. Geometrical isomerism: cis–trans and syn-anti isomerism, E/Z notations with Cahn Ingold and Prelog (CIP) rules for determining absolute configuration. Optical Isomerism: Optical Activity, Specific Rotation, Chirality/Asymmetry, Enantiomers, Molecules with two or more chiral-centres, Distereoisomers, Meso structures, Racemic mixture. Resolution of Racemic mixtures. Relative and absolute configuration: D/L and R/S designations. Coverage: 1. Types of Isomers : Comparing Structures 2. Optical Activity 3. Racemic Mixtures : Separation of Racemic Mixtures 4. Enantiomeric Excess and Optical Purity 5. Relative and Absolute Configuration 6. Physical and Chemical Properties of Stereoisomers 2 Stereochemistry Types of Isomers Dr. Rajeev Ranjan 3 Stereochemistry Determining the Relationship Between Two Non-Identical Molecules Dr. Rajeev Ranjan 4 Stereochemistry Comparing Structures: Are the structures connected the same? yes no Are they mirror images? Constitutional Isomers yes no Enantiomers Enantiomers Is there a plane of symmetry? All chiral centers will be opposite between them. yes no Meso Diastereomers superimposable Dr. Rajeev Ranjan 5 Stereochemistry Optical Activity: • The chemical and physical properties of two enantiomers are identical except in their interaction with chiral substances. • The physical property that differs is the behavior when subjected to plane-polarized light ( this physical property is often called an optical property). • Plane-polarized (polarized) light is light that has an electric vector that oscillates in a single plane.
    [Show full text]
  • Cross-Linked Protein Crystal Technology in Bioseparation and Biocatalytic Applications
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Aaltodoc Helsinki University of Technology, Department of Chemical Technology Technical Biochemistry Report 1/2004 Espoo 2004 TKK-BE-8 CROSS-LINKED PROTEIN CRYSTAL TECHNOLOGY IN BIOSEPARATION AND BIOCATALYTIC APPLICATIONS Antti Vuolanto Dissertation for the degree of Doctor in Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE 2 (Komppa Auditorium) at Helsinki University of Technology (Espoo, Finland) on the 20th of August, 2004, at 12 noon. Helsinki University of Technology Department of Chemical Technology Laboratory of Bioprocess Engineering Teknillinen korkeakoulu Kemian osasto Bioprosessitekniikan laboratorio Distribution: Helsinki University of Technology Laboratory of Bioprocess Engineering P.O. Box 6100 FIN-02015 HUT Tel. +358-9-4512541 Fax. +358-9-462373 E-mail: [email protected] ©Antti Vuolanto ISBN 951-22-7176-1 (printed) ISBN 951-22-7177-X (pdf) ISSN 0359-6621 Espoo 2004 Vuolanto, Antti. Cross-linked protein crystal technology in bioseparation and biocatalytic applications. Espoo 2004, Helsinki University of Technology. Abstract Chemical cross-linking of protein crystals form an insoluble and active protein matrix. Cross-linked protein crystals (CLPCs) have many excellent properties including high volumetric activity and stability. In this thesis CLPC technology was studied in bioseparation and biocatalytic applications. A novel immunoaffinity separation material, cross-linked antibody crystals (CLAC), was developed in this thesis for enantiospecific separation of a chiral drug, finrozole. Previously, the preparation of an antibody Fab fragment ENA5His capable of enantiospecific affinity separation of the chiral drug has been described.
    [Show full text]
  • Enzyme Supported Crystallization of Chiral Amino Acids
    ISBN 978-3-89336-715-3 40 Band /Volume Gesundheit /Health 40 Gesundheit Enzyme supported crystallization Health Kerstin Würges of chiral amino acids Mitglied der Helmholtz-Gemeinschaft Kerstin Würges Kerstin aminoacids Enzyme supported ofchiral crystallization Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 Forschungszentrum Jülich GmbH Institute of Bio- and Geosciences (IBG) Biotechnology (IBG-1) Enzyme supported crystallization of chiral amino acids Kerstin Würges Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 ISSN 1866-1785 ISBN 978-3-89336-715-3 Bibliographic information published by the Deutsche Nationalbibliothek. The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de. Publisher and Forschungszentrum Jülich GmbH Distributor: Zentralbibliothek 52425 Jülich Phone +49 (0) 24 61 61-53 68 · Fax +49 (0) 24 61 61-61 03 e-mail: [email protected] Internet: http://www.fz-juelich.de/zb Cover Design: Grafische Medien, Forschungszentrum Jülich GmbH Printer: Grafische Medien, Forschungszentrum Jülich GmbH Copyright: Forschungszentrum Jülich 2011 Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 D 61 (Diss. Düsseldorf, Univ., 2011) ISSN 1866-1785 ISBN 978-3-89336-715-3 The complete volume ist freely available on the Internet on the Jülicher Open Access Server (JUWEL) at http://www.fz-juelich.de/zb/juwel Neither this book nor any part of it may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
    [Show full text]
  • APPLICATIONS in ASYMMETRIC SYNTHESIS Carlos
    324 SYNTHESIS OF OCTAHYDROBENZO - 1, 2,3 - DIAZAPHOSPHOLIDINE - 2 - OXIDES AND THEIR DERIVATIVES: APPLICATIONS IN ASYMMETRIC SYNTHESIS DOI: http://dx.medra.org/ 10.17374/targets.2020.23.324 Carlos Cruz - Hernández a , José M. Landeros a , Eusebio Juaristi * a,b a Departamento de Química, Centro de Investigación y de E studios Avanzados, Avenida IPN 2508, 07360 Ciudad de México, Mexico b El Colegio Nacional, Luis González Obregón 23, Centro Histórico, 06020 Ciudad de México, Mexico (e - mail: [email protected]; [email protected]) Abstract. This chapter outlines recent efforts devoted to the synthesis of heterocycles that include the octahydrobenzo - 1,3,2 - diazaphospholidine - 2 - oxide fragment, as well as their application in asymmetri c synthesis. The first part of this review provides a brief discussion of the general structural characteristics of this phosphorus - containing heterocyclic scaffold. The second part describes the synthetic paths that were undertaken to synthesize the desir ed heterocycles , as well as some relevant considerations pertaining the spectroscopic characterization of the phosphorus - containing heterocycles of interest . The third part provides several illustrative examples where the novel chiral heterocycles were employed in ena ntioselective synthesis. The new phosphorus - containing heterocycles proved useful : i) as chiral auxiliaries in nucleophilic addition reactions, as well as as imine activators in electrophilic addition reactions; ii ) as c hiral ligands i n nucleophilic allylation and crotonylation of prochiral aldehydes , and iii) as c hiral organocatalysts in enantioselective aldol, Michael, and cascade reactions. Contents 1. Introduction 2. Synthesis of the octahydrobenzo - 1,3,2 - diazaphospho lidine - 2 - oxide s 2.1 . Conformational and configurational assignments 3 .
    [Show full text]
  • Spherezymes: a Novel Structured Self-Immobilisation Enzyme
    BMC Biotechnology BioMed Central Research article Open Access Spherezymes: A novel structured self-immobilisation enzyme technology Dean Brady*1, Justin Jordaan1, Clinton Simpson1, Avashnee Chetty2, Cherise Arumugam2 and Francis S Moolman2 Address: 1CSIR Biosciences, Ardeer Road, Modderfontein, 1645 South Africa and 2CSIR Materials Science and Manufacturing, Meiring Naudé Road, Brummeria, Pretoria, 0001 South Africa Email: Dean Brady* - [email protected]; Justin Jordaan - [email protected]; Clinton Simpson - [email protected]; Avashnee Chetty - [email protected]; Cherise Arumugam - [email protected]; Francis S Moolman - [email protected] * Corresponding author Published: 31 January 2008 Received: 8 May 2007 Accepted: 31 January 2008 BMC Biotechnology 2008, 8:8 doi:10.1186/1472-6750-8-8 This article is available from: http://www.biomedcentral.com/1472-6750/8/8 © 2008 Brady et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Enzymes have found extensive and growing application in the field of chemical organic synthesis and resolution of chiral intermediates. In order to stabilise the enzymes and to facilitate their recovery and recycle, they are frequently immobilised. However, immobilisation onto solid supports greatly reduces the volumetric and specific activity of the biocatalysts. An alternative is to form self-immobilised enzyme particles. Results: Through addition of protein cross-linking agents to a water-in-oil emulsion of an aqueous enzyme solution, structured self-immobilised spherical enzyme particles of Pseudomonas fluorescens lipase were formed.
    [Show full text]
  • Absolute Configuration Determination
    Chirality in Pharmaceutical Compounds and Absolute Configuration Determination Crystallization: Screening, Application & Process Development X-ray Diffraction Unit Jordi Benet-Buchholz Barcelona, 11 April 2019 Institut Català d’Investigació Química Av. Països Catalans 16 1 43007 Tarragona (Spain) From chiral crystals to the absolute configuration of molecules: Is it an easy way? (–)-Galiellalactone *S OH R * *S O O *R Orthorhombic , P 2 2 2 Absolute configuration: 1 1 1 R1: 3,45 % 4S, 5aR, 7aR, 7bS Flack: 0.01(19) Hooft/Parsons: -0.06(04)/-0.04(05) • F. Nussbaum, R. Hanke, T. Fahrig, J. Benet-Buchholz; Eur. J. Org. Chem. 2004, 2783-2790. 2 Determination of Absolute Configuration of APIs Definitions in Chirality Precedents Methodologies Single Crystal X-ray Structure Determination: Background Candidate samples Sample and Crystal selection Validation and measurements Examples Final schedule 3 Chirality Definitions in Chirality: An object or a system is chiral if it is distinguishable from its mirror image; that is, it cannot be superposed onto it. The word chirality is derived from the Greek word meaning “hand” Paula Benet The most universally recognized example for chirality are the human hands. Live is chiral 4 Chirality Definitions in Chirality: - Each molecule which cannot be superposed with its mirror image is “chiral”. - Molecules with a mirror plane are called “achiral”. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom (four different substituents) Two mirror images of a chiral molecule are called enantiomers or optical isomers Foto cristall papallona 5 Conglomerate of crystals forming enantiomeric butterflies Chirality Definitions in Chirality: Pairs of enantiomers are often designated as “right- or left-handed”.
    [Show full text]
  • Absolute Configuration Some Definitions
    Absolute Structure Absolute Configuration Some definitions • Absolute Configuration -> spatial arrangement of the atoms for a chiral molecule (R/S, P/M or D/L assignment). • Absolute Structure -> spatial arrangement of atoms in a noncentrosymmetric crystal structure (unit-cell, space group) • Chiral molecules Molecules that cannot be superimposed with their mirror image • Two mirror images of a chiral molecule are called enantiomers, they are optical isomers • Determination of absolute configuration -> handness of the molecule Origin of chirality • Asymmetric carbon atoms (R/S) • Axial chirality R-Binol S-Binol • Chiral Propeller Arrangement (P/M or / ) Helicenes In the solid state • Chiral molecules can crystallize as an enantiopure bulk sample or as a racemic mixture. • For enantiopure crystals Space group restriction: Only 65 space groups allowed for chiral molecules: No Inversion Center / No Mirror / No Glide Plane These include 11 pairs of eniantomorph space groups (screw axes of opposite handedness) eg: P41/P43 or P61/P65 Space Group Restrictions 85 % Racemic mixture In the solid state • 1) Conglomerate: a mixture of well-resolved crystals of both enantiomers Chiral space group Individual crystals have an optical activity 5-10 % • 2) Racemates: One type of crystal containing the two enantiommers in a well defined stoechiometry. No optical activity Usually centrosymmetric space group 90-95 % Conglomerate Racemates Racemic mixture In the solid state • 3) Inversion twin : twinned crystals of both enantiomers Chiral space group • 4)
    [Show full text]
  • 1 Fundamentals of the Stereochemistry of Organophosphorus Compounds
    1 1 Fundamentals of the Stereochemistry of Organophosphorus Compounds 1.1 Historical Background Natural processes are subordinate to geometrodynamics – the theory describing physical objects, geometrical spacetime, and associated phenomena completely in terms of geometry, and her elder sister – symmetry. Symmetry/asymmetry is one of the basic concepts in modern natural science [1]. Research into this field began in the Middle Ages, when the birefringent properties of calcite were discovered. In 1669, Bartholinus observed the double refractive properties of the calcite Iceland spar. Later, in 1801, the mineralogist Haui found that quartz crystals are enantiomorphic, representing mirror images of one another. In 1815, another French naturalist J.-B. Biot discovered that certain chemical compounds rotate the plane of a beam of polarized light [2]. Biot constructed the first polarimeter and he also discovered that many natural compounds exhibit optical activity, that is, they rotate the plane of circularly polarized light. Studying crystals under a microscope, Biot discovered two types of crystals. The sample consisting of crystals of one type turned polarized light clockwise and that from another type in the opposite direction. A mixture of the two types of crystals had a neutral effect on polar- ized light. The nature of this property remained a mystery until 1848, when Louis Pasteur proposed that it had a molecular basis originating from some form of dissymmetry [3]. Pasteur separated the left and right hemihedral crystals of the sodium-ammonium salt of D,L-tartaric acid under a microscope, and connected the opposite optical activity to the mirror image of these crystals. Pasteur termed the mixture creating polarization as dissymetric and the phenomenon as dissymmetry (asymmetry).
    [Show full text]
  • Distinction of Enantiomers by NMR
    REVIEWS Disinction of enantiomers by NMR spectroscopy using chiral orienting media Burkhard Luy Abstract | NMR spectroscopy is a very important analytical tool in modern organic and inorganic chemistry. Next to the identification of molecules and their structure determination, it is also used for the distinction of enantiomers and the measurement of enantiomeric purity. This article gives a brief review of the techniques being developed for enantiomeric differentiation by virtue of chiral alignment media and their induction of enantiomerically dependent anisotropic NMR parameters like residual dipolar couplings. An overview of existing chiral alignment media, a brief introduction into the basic theory and measurement of the various anisotropic parameters, and several example applications are given. 1. Introduction valuable compounds one doesn’t necessarily want to NMR spectroscopy is one of the most important irreversibly modify the substance. analytical tools in modern organic and inorganic Another possibility for the distinction of chemistry as it is the only tool that allows the enantiomers is the orientation of the molecule of determination of molecular structures at atomic interest in a so-called chiral alignment medium. resolution in solution. It is used to identify the In this case, the molecule is partially aligned constitution, conformation and configuration and anisotropic NMR parameters like residual of countless molecules every day. However, the quadrupolar couplings, residual dipolar couplings magnetic field used for the induction of the Zeeman and residual chemical shift anisotropy can be splitting is per se achiral so that enantiomers measured2–4. As the orientation in a chiral have identical properties and therefore identical alignment medium is different for the two NMR spectra.
    [Show full text]
  • Identifying a Diastereomeric Salt for a Challenging Chiral Resolution
    APPLICATION NOTE Identifying a diastereomeric salt for a challenging chiral resolution Advancing a therapeutic for MMV used Unchained Lab’s high-throughput malaria using the Big Kahuna techniques to deliver successful results in system approximately two weeks to a problem that Researchers at the Medicines for Malaria Ven- they had been trying to solve for more than one year using traditional methods. ture were pursuing a promising candidate for the treatment of malaria when they ran into a road- block. For over a year they attempted to develop a more direct method for isolating a key chiral The mission of MMV is to reduce the burden of intermediate. Until this challenge was overcome, malaria in disease-endemic countries by dis- the program was stalled and could not progress. covering, developing and facilitating the delivery Leveraging the power of Unchained Labs' Big Kahuna of new, effective and affordable anti-malarial system configured for preformulation, they over- drugs. They envision a world in which innovative came this roadblock by identifying and scaling-up medicines will cure and protect the vulnerable a viable chiral resolution method in just two and under-served populations at risk of malar- weeks. ia, and help to ultimately eradicate this terrible disease. In 1999, there were no compounds in the MMV portfolio. Ten years later, MMV had a The Medicines for Malaria robust portfolio consisting of 42 development Venture programs, including four anti-malarial com- Worldwide, 3.3 billion people are at risk for pounds in Phase 3 clinical trials and three com- malaria, which is prevalent in tropical and pounds in registration—all funded solely by MMV.
    [Show full text]
  • The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts
    S S symmetry Article The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts Dorottya Fruzsina Bánhegyi and Emese Pálovics * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected] Abstract: Knowing the eutectic composition of the binary melting point phase diagrams of the diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, flexibility and complementarity. Citation: Bánhegyi, D.F.; Pálovics, E.
    [Show full text]