II. Stereochemistry 5
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Separation of the Mixtures of Chiral Compounds by Crystallization
1 Separation of the Mixtures of Chiral Compounds by Crystallization Emese Pálovics2, Ferenc Faigl1,2 and Elemér Fogassy1* 1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 2Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, Budapest, Hungary 1. Introduction Reaction of a racemic acid or base with an optically active base or acid gives a pair of diastereomeric salts. Members of this pair exhibit different physicochemical properties (e.g., solubility, melting point, boiling point, adsorbtion, phase distribution) and can be separated owing to these differences. The most important method for the separation of enantiomers is the crystallization. This is the subject of this chapter. Preparation of enantiopure (ee~100%) compounds is one of the most important aims both for industrial practice and research. Actually, the resolution of racemic compounds (1:1 mixture of molecules having mirror-imagine relationship) still remains the most common method for producing pure enantiomers on a large scale. In these cases the enantiomeric mixtures or a sort of their derivatives are separated directly. This separation is based on the fact that the enantiomeric ratio in the crystallized phase differs from the initial composition. In this way, obtaining pure enantiomers requires one or more recrystallizations. (Figure 1). The results of these crystallizations (recrystallizations) of mixtures of chiral compounds differ from those observed at the achiral compounds. Expectedly, not only the stereoisomer in excess can be crystallized, because the mixture of enantiomers (with mirror image relationship) follows the regularities established from binary melting point phase diagrams, and ternary composition solubility diagrams, respectively, as a function of the starting enantiomer proportion. -
Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation Of
Perspective Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation of Enantiomers and Enantiomeric Mixtures Emese Pálovics *, Dorottya Fruzsina Bánhegyi and Elemér Fogassy Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] (D.F.B.); [email protected] (E.F.) * Correspondence: [email protected]; Tel.: +36-1-4632101 Received: 3 August 2020; Accepted: 14 September 2020; Published: 21 September 2020 Abstract: This perspective is focused on the main parameters determining the results of crystallization of enantiomers or enantiomeric mixtures. It was shown that the ratio of supramolecular and helical associations depends on the eutectic composition of the corresponding enantiomeric mixture. The M and P ratios together with the self-disproportionation (SDE) of enantiomers define the reaction of the racemic compound with the resolving agent. Eventually, each chiral molecule reacts with at least two conformers with different degrees of M and P helicity. The combined effect of the configuration, charge distribution, constituent atoms, bonds, flexibility, and asymmetry of the molecules influencing their behavior was also summarized. Keywords: chiral molecules; enantiomeric separation; self-disproportionation of enantiomers; supramolecular associations; helical structure; eutectic composition 1. Introduction The preparation of asymmetric (chiral) compounds (enantiomers) is one of the main goals of research, industry and medicine. The preparation of a given enantiomer is possible in several ways, for example by selective synthesis, which requires the separation of the chiral catalyst or the enantiomers of the racemic compound, and in which case a resolving agent (like a chiral catalyst) may be required. -
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. -
The Racemate-To-Homochiral Approach to Crystal Engineering Via Chiral Symmetry-Breaking
CrystEngComm The Racemate -to -Homochiral Approach to Crystal Engineering via Chiral Symmetry-Breaking Journal: CrystEngComm Manuscript ID: CE-HIG-02-2015-000402.R1 Article Type: Highlight Date Submitted by the Author: 04-Apr-2015 Complete List of Authors: An, Guanghui; Heilongjiang University, School of Chemistry and Materials Science Yan, Pengfei; Heilongjiang University, School of Chemistry and Materials Science Sun, Jingwen; Heilongjiang University, School of Chemistry and Materials Science Li, Yuxin; School of Chemsitry and Materials Science of Heilongjiang University, Yao, Xu; Heilongjiang University, School of Chemistry and Materials Science Li, Guangming; School of Chemsitry and Materials Science of Heilongjiang University, Page 1 of 12Journal Name CrystEngComm Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE The Racemate-to-Homochiral Approach to Crystal Engineering via Chiral Symmetry-Breaking Guanghui An, a Pengfei Yan, a Jingwen Sun, a Yuxin Li, a Xu Yao, a Guangming Li,* a Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x The racemate-to-homochiral approach is to transform or separate the racemic mixture into homo chiral compounds. This protocol, if without an external chiral source, is categorized into chiral symmetry- breaking. The resolution processes without chiral induction are highly important for the investigation on the origin of homochirality in life, pharmaceutical synthesis, chemical industrial and material science. 10 Besides the study on the models and mechanisms to explain the racemate-to-homochiral approach which may give the probable origin of homochirality in life, the recent developments in this field have been plotted towards the separation of enantiomers for the synthesis of pharmaceuticals, chiral chemicals. -
Enantiomers & Diastereomers
Chapter 5 Stereochemistry Chiral Molecules Ch. 5 - 1 1. Chirality & Stereochemistry An object is achiral (not chiral) if the object and its mirror image are identical Ch. 5 - 2 A chiral object is one that cannot be superposed on its mirror image Ch. 5 - 3 1A. The Biological Significance of Chirality Chiral molecules are molecules that cannot be superimposable with their mirror images O O ● One enantiomer NH causes birth defects, N O the other cures morning sickness O Thalidomide Ch. 5 - 4 HO NH HO OMe Tretoquinol OMe OMe ● One enantiomer is a bronchodilator, the other inhibits platelet aggregation Ch. 5 - 5 66% of all drugs in development are chiral, 51% are being studied as a single enantiomer Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs Ch. 5 - 6 2. Isomerisom: Constitutional Isomers & Stereoisomers 2A. Constitutional Isomers Isomers: different compounds that have the same molecular formula ● Constitutional isomers: isomers that have the same molecular formula but different connectivity – their atoms are connected in a different order Ch. 5 - 7 Examples Molecular Constitutional Formula Isomers C4H10 and Butane 2-Methylpropane Cl Cl C3H7Cl and 1-Chloropropane 2-Chloropropane Ch. 5 - 8 Examples Molecular Constitutional Formula Isomers CH O CH C H O OH and 3 3 2 6 Ethanol Methoxymethane O OCH and 3 C H O OH 4 8 2 O Butanoic acid Methyl propanoate Ch. 5 - 9 2B. Stereoisomers Stereoisomers are NOT constitutional isomers Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. -
Chapter 4: Stereochemistry Introduction to Stereochemistry
Chapter 4: Stereochemistry Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane Me Me Me C Me H Bu Bu Me Me 2-methylhexane H H mirror Me rotate Bu Me H 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane H C Et Et Me Pr Pr 3-methylhexane Me Me H H mirror Et rotate H Me Pr 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane .Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means "handed") 3-methylhexane is a chiral molecule. .Compounds that are superimposable with their mirror image are called achiral. 2-methylhexane is an achiral molecule. .An atom (usually carbon) with 4 different substituents is called a stereogenic center or stereocenter. Enantiomers Et Et Pr Pr Me CH3 Me H H 3-methylhexane mirror enantiomers Et Et Pr Pr Me Me Me H H Me H H Two compounds that are non-superimposable mirror images (the two "hands") are called enantiomers. Introduction To Stereochemistry Structural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity (structure, constitution) 2-methylpentane 3-methylpentane Conformational Isomers - Compounds of the same structure that differ in rotation around one or more single bonds Me Me H H H Me H H H H Me H Configurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or more aspects of stereochemistry (how groups are oriented in space - enantiomers or diastereomers) We need a a way to describe the stereochemistry! Me H H Me 3-methylhexane 3-methylhexane The CIP System Revisited 1. -
Chirality and Enantiomers
16.11.2010 Bioanalytics Part 5 12.11.2010 Chirality and Enantiomers • Definition: Optical activity • Properties of enantiomers • Methods: – Polarimetry – Circular dichroism • Nomenclature • Separation of enantiomers • Determination of enantiomeric excess (ee) Determination of absolute configuration • Enantiomeric ratio (E‐value) 1 16.11.2010 Definitions Enantiomers: the two mirror images of a molecule Chirality: non‐superimposable mirror‐images •Depends on the symmetry of a molecule •Point‐symmetry: asymmetric C, Si, S, P‐atoms •Helical structures (protein α‐helix) Quarz crystals snail‐shell amino acids Properties of Enantiomers – Chemical identical – Identical UV, IR, NMR‐Spectra – Differences: • Absorption and refraction of circular polarized light is different – Polarimetry, CD‐spectroscopy • Interaction with other chiral molecules/surfaces is different – Separation of enantiomers on chiral columns (GC, HPLC) 2 16.11.2010 Chiral compounds show optical activity A polarimeter is a device which measures the angle of rotation by passing polarized light through an „optical active“ (chiral) substance. Interaction of light and matter If light enters matter, its intensity (amplitude), polarization, velocity, wavelength, etc. may alter. The two basic phenomena of the interaction of light and matter are absorption (or extinction) and a decrease in velocity. 3 16.11.2010 Interaction of light and matter Absorption means that the intensity (amplitude) of light decreases in matter because matter absorbs a part of the light. (Intensity is the square of amplitude.) Interaction of light and matter The decrease in velocity (i.e. the slowdown) of light in matter is caused by the fact that all materials (even materials that do not absorb light at all) have a refraction index, which means that the velocity of light is smaller in them than in vacuum. -
Magnetic Combined Cross-Linked Enzyme Aggregates of Ketoreductase and Alcohol Dehydrogenase
catalysts Article Magnetic Combined Cross-Linked Enzyme Aggregates of Ketoreductase and Alcohol Dehydrogenase: An Efficient and Stable Biocatalyst for Asymmetric Synthesis of (R)-3-Quinuclidinol with Regeneration of Coenzymes In Situ Yuhan Chen 1, Qihua Jiang 1, Lili Sun 1, Qiang Li 2, Liping Zhou 1, Qian Chen 1, Shanshan Li 1, Mingan Yu 1 and Wei Li 1,3,* 1 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China; [email protected] (Y.C.); [email protected] (Q.J.); [email protected] (L.S.); [email protected] (L.Z.); [email protected] (Q.C.); [email protected] (S.L.); [email protected] (M.Y.) 2 Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical engineering, Chongqing University of Education, Chongqing 400067, China; [email protected] 3 Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, China * Correspondence: [email protected]; Tel.: +86-23-6848-5161 Received: 14 July 2018; Accepted: 30 July 2018; Published: 15 August 2018 Abstract: Enzymes are biocatalysts. In this study, a novel biocatalyst consisting of magnetic combined cross-linked enzyme aggregates (combi-CLEAs) of 3-quinuclidinone reductase (QNR) and glucose dehydrogenase (GDH) for enantioselective synthesis of (R)-3-quinuclidinolwith regeneration of cofactors in situ was developed. The magnetic combi-CLEAs were fabricated with the use of ammonium sulfate as a precipitant and glutaraldehyde as a cross-linker for direct immobilization of QNR and GDH from E. coli BL(21) cell lysates onto amino-functionalized Fe3O4 nanoparticles. The physicochemical properties of the magnetic combi-CLEAs were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and magnetic measurements. -
Preferential Crystallization of a Racemic Compound Via Its Conglomerate Co-Crystals
Preferential crystallization of a racemic compound via its conglomerate co-crystals Master Thesis Oscar F. Villamil R August 24th 2016 Faculty of 3ME Department: Process & Energy Section: Intensified Reaction & Separation Systems Graduation Committee Ir. W. Li PDeng Dr. ir. H.J.M Kramer Dr. ir. H.W.Nugteren Dr. ir. A. van der Heijden 1 Abstract Preferential crystallization, as a powerful chiral resolution technique, is intrinsically limited to chiral molecules that crystallize as conglomerates. Many studies have been conducted on using chemical reactions to convert the target molecules, which originally form racemic compounds, into conglomerate-forming derivatives salts or by creating solvate, for the application of preferential crystallization. Up to this date conglomerate co-crystals of racemic compounds have never been applied as the intermediate for chiral resolution. In this study, preferential crystallization of the model compound Ibuprofen (IBU), originally a racemic compound, was carried out via its conglomerate co-crystal with 2,4-bipyridine ethylene (BPE) in heptane. Suitable operation conditions were selected based on pseudo- binary phase diagram of the model compound system constructed under different IBU-BPE ratio. A unique measurement method combining polarimeter and Nuclear Magnetic Resonance (NMR) measurements was developed to identify the enantiopurity and the yield of the final product, which was a mixture of racemic IBU and IBU-BPE co-crystals, a likely result from this complex system. With respect to the results, preferential crystallization of IBU was successfully performed by slowly cooling down a saturated solution of racemic IBU-BPE, initially at T=57.5°C, after seeding it with S-IBU/BPE crystals to T=53°C with a cooling rate of 0.3°C/min. -
Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling
Highly enantioselective synthesis of γ-, δ-, and e-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling Shiqing Xu, Akimichi Oda, Hirofumi Kamada, and Ei-ichi Negishi1 Department of Chemistry, Purdue University, West Lafayette, IN 47907 Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved May 2, 2014 (received for review January 21, 2014) Despite recent advances of asymmetric synthesis, the preparation shown in Schemes 1 and 2 illustrate the versatility of ZACA of enantiomerically pure (≥99% ee) compounds remains a chal- represented by the organoaluminum functionality of the ini- lenge in modern organic chemistry. We report here a strategy tially formed ZACA products. Introduction of the OH group for a highly enantioselective (≥99% ee) and catalytic synthesis by oxidation of initially formed alkylalane intermediates in of various γ- and more-remotely chiral alcohols from terminal Scheme 2 is based on two considerations: (i) the proximity of the alkenes via Zr-catalyzed asymmetric carboalumination of alkenes OH group to a stereogenic carbon center is highly desirable for (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ lipase-catalyzed acetylation to provide ultrapure (≥99% ee) di- oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols functional intermediates, and (ii) the versatile OH group can R S α ω produced both ( )- and ( )- , -dioxyfunctional intermediates (3) be further transformed to a wide range of carbon groups by – ee ≥ ee in 80 88% , which were readily purified to the 99% level tosylation or iodination followed by Cu- or Pd-catalyzed cross- by lipase-catalyzed acetylation through exploitation of their high α ω coupling. -
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. -
A Review on Chiral Chromatography and Its Application to the Pharmaceutical Industry
Chemsearch Journal 2(1): 8 - 11 Publication of Chemical Society of Nigeria, Kano Chapter CHIRAL CHROMATOGRAPHY AND ITS APPLICATION TO THE PHARMACEUTICAL INDUSTRY: A REVIEW Mudi, S. Y. and *Muhammad, A. Department of Pure and Industrial Chemistry, Bayero University, PMB 3011, Kano. *Correspondence author: [email protected] ABSTRACT Chiral chromatographic enantioseparation has been in practice by researchers. There has been a considerable interest in the synthesis and separation of enantiomers of organic compounds especially because of their importance in the biochemical and pharmaceutical industries. Often, these compounds are purified rather than being produced by chiral-specific synthesis. We herein present a general discussion that focuses on the chromatographic enantioseparation, which we hope will be useful to chromatographic and pharmaceutical industries. Keywords: Chiral chromatography, enantioseparation, pharmaceutical industry. INTRODUCTION giving differing affinities between the analytes Chromatography is the collective term for a set of (Schreier et al., 1995). laboratory techniques for the separation of mixtures. It The main goal of this review is to provide a brief involves passing a mixture dissolved in a "mobile overview of chiral separations to researchers who phase" through a “stationary phase”, which separates are versed in the area of analytical separations but the analyte from other compounds in the mixture unfamiliar with chiral separations. This review based on differential partitioning between the mobile highlights significant issues of the chiral and stationary phases. Subtle differences in a separations and provides salient examples from compound's partition coefficient result in differential specific classes of chiral selectors where retention on the stationary phase and thus effecting appropriate. the separation (Laurence and Christopher, 1989; Pascal et al., 2000).