DOCSLIB.ORG

Chiral Resolution and Deracemization Through Co-Crystallization

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chiral Resolution and Deracemization Through Co-Crystallization Chiral resolution and deracemization through co-crystallization Crystallization workshop Barcelona, 11 th March 2019 Tom Leyssens 2 Personal Expertise! 2.5y, Automation Team Leader UCB Pharma (2007-2009) Process optimization (Crystallization process) Polymorphism issues, optimization, purity, crystal form, PSD, … 3 Personal Expertise! UCL Professor in Physical chemistry (2009-…) ?? Citric acid Mandelic acid Caffeine … Isonicotinamide ?? 4 Chirality and drug compounds 60% of all drug compounds contain at least one chiral center Enantiomers ≠ biological properties V Regulatory instances push towards the development of enantiopure drugs 5/1 1 Chirality and drug compounds Less costly process Resolution by entrainment Only for conglomerates Less costly process Diastereomeric salt formation But only for compounds that can form salts Chiral chromatography Used for many compounds Expensive technique 6 Chirality and drug compounds Entrainment Enantiospecific Deracemizat. 7 Resolution by entrainment/ preferential crystallization 8 1. Resolution by entrainment V Entrainment Enantiospecific Deracemizat. CaCl 2, MgCl 2, ZnCl 2 Selectracetam, Brivaracetam, Piracetam, …. CrystEngComm 2014 , 5887 . 9 *O. Shemshuk, L. Song, Chem. Comm., 2018 . 1. Resolution by entrainment V Entrainment Enantiospecific Deracemizat. ETI and LEV co-crystals have different stoichiometry!! No other forms identified 10 1. Resolution by entrainment Lev.ZnCl 2 Eti 2.ZnCl 2 V Entrainment Enantiospecific Deracemizat. Lev·ZnCl calc. 2 Lev·ZnCl exp. 2 5 10 15 20 25 30 35 40 45 50 2θ / deg Simulated and experimental XRPD match 11 1. Resolution by entrainment LEV + ZnCl 2 1:1 V Entrainment Enantiospecific Deracemizat. LEV.ZnCl 2 + ZnCl 2 LEV.ZnCl 2 ZnCl 2 12 1. Resolution by entrainment ETI + ZnCl 2 2:1 V Entrainment Enantiospecific Deracemizat. Thermodynamically stable ETI 2.ZnCl 2 racemic compound + 1 eq. ETI + 1 eq. ZnCl 2 LEV(S).ZnCl 2 Thermodynamically stable conglomerate DEV(S).ZnCl 2 !!Reversible stoichiometric switch!! 13 1. Resolution by entrainment Understand the solid state thermodynamics (Phase Diagram) ZnCl 2 Single Phases V Entrainment 1:1 (S) + 1:1 (R) Mixture of 2 phases + ZnCl Enantiospecific 2 Mixture of 3 phases Deracemizat. (1:1)-R 1:1 (R) + 1:1 (S) (1:1)-S 2:1+ 1:1 (S) + 1:1 (R) 2:1+ 1:1 (R) + (2:1) 2:1+ 1:1 (S) + R-ETI S-ETI RS-ETI + + RS-ETI 2:1+ RS-ETI 2:1+ RS-ETI 2:1 +R-ETI +S-ETI R-ETI RS-ETI+ R-ETI RS -ETI RS-ETI+ S-ETI S-ETI 14 1. Resolution by entrainment Solvent included V Entrainment Enantiospecific Deracemizat. Importance of this PD: when adding solvent, one can only get one of the combinations shown above in suspension eg. 2:1 + 1:1 (R) + 1:1 (S) 2:1 + ZnCl2 15 1. Resolution by entrainment Solvent included V Entrainment Enantiospecific Deracemizat. Importance of this PD: when adding solvent, one can only get one of the combinations shown above in suspension eg. 1:1 (R) + 1:1 (S) 16 1. Resolution by entrainment Solvent Stable racemic compound Stable conglomerate V Entrainment Enantiospecific ETI 2:1 Deracemizat. 1:1 (S) 1:1 (S) + 1:1 (R) +2:1 ZnCl2 ETI +2:1 + 1:1 (R) 1:1 (S) + 1:1 (R) + ZnCl2 ETI 2:1 ZnCl2 Based on reasoning only Stoichiometric switch also holds in suspension 17 1. Resolution by entrainment Solvent Stable racemic compound Stable conglomerate V Entrainment Enantiospecific ETI 2:1 Deracemizat. 1:1 (S) 1:1 (S) + 1:1 (R) +2:1 ZnCl2 ETI +2:1 + 1:1 (R) 1:1 (S) + 1:1 (R) + ZnCl2 ETI 2:1 ZnCl2 Theory and experiment allign !!! In zone V, resolution by entrainment becomes possible!! 18 1. Resolution by entrainment Make ternary phase diagrams. V Entrainment Enantiospecific Deracemizat. XXXXXXXXX 19 Resolution by Diasteriomeric/enantiospecific co-crystal formation 20 Chirality and drug compounds Less costly process Resolution by entrainment Only for conglomerates Less costly process Entrainment Diastereomeric salt formation But only for compounds that can form salts V Enantiospec. Deracemizat. Chiral chromatography Used for many compounds Expensive technique 21 2. Enantiospecific/diasteriomeric resolution Levetiracetam Just make some co-crystals, get some structures and this will get us a publication …. Entrainment ?? V Enantiospec. Citric acid Deracemizat. Mandelic acid Caffeine … Isonicotinamide 22 2. Enantiospecific/diasteriomeric resolution Entrainment V Enantiospec. Deracemizat. …. ∆G of a few kcal.mol -1 , while for salts this goes up to 50 kcal.mol -1. Only 10% succesrate for cocrystals Difficult to become predictive TRIAL AND ERROR APPROACH!!! 23 *G. Springuel, T. Leyssens, CrystGrowth Des. 2012-2015 . 2. Enantiospecific/diasteriomeric resolution O NH2 Piracetam N Levetiracetam O Co-crystals Co-crystals D-tartaric acid 1:1 D-tartaric acid 1:1 citric acid 1:1 Entrainment V Enantiospec. citric acid 3:2 Deracemizat. Mandelic acid (racemic) 2:1 Mandelic acid (racemic) 1:1 R-mandelic acid 2:1 S-mandelic acid 1:1 p-hydroxy-benzoic acid 1:1 2,3-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,5-dihydroxy-benzoic acid 1:1 4 co-crystals 3,4-dihydroxy-benzoic acid 1:1 3,5-dihydroxy-benzoic acid 1:1 40% Succesrate 11 co-crystals with 10 24 different acids 2. Enantiospecific/diasteriomeric resolution Piracetam Levetiracetam Co-crystals Co-crystals D-tartaric acid 1:1 D-tartaric acid 1:1 citric acid 1:1 Entrainment V Enantiospec. citric acid 3:2 Deracemizat. Mandelic acid (racemic) 2:1 Mandelic acid (racemic) 1:1 R-mandelic acid 2:1 S-mandelic acid 1:1 p-hydroxy-benzoic acid 1:1 2,3-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,5-dihydroxy-benzoic acid 1:1 O 3,4-dihydroxy-benzoic acid 1:1 (S,S) NH 3,5-dihydroxy-benzoic acid 1:1 2 N O (S,R) 25 2. Enantiospecific/diasteriomeric resolution Piracetam Co-crystals: Entrainment V Enantiospec. S-tartaric acid R-tartaric acid Deracemizat. S-Mandelic acid R-Mandelic acid 26 26 2. Enantiospecific/diasteriomeric resolution O NH2 N O Levetiracetam Co-crystals: Entrainment V Enantiospec. S-tartaric acid R-tartaric acid Deracemizat. S-mandelic R-mandelic 27 27 2. Enantiospecific/diasteriomeric resolution Entrainment V Enantiospec. Deracemizat. AND NOW WHAT??? 28 2. Enantiospecific/diasteriomeric resolution Entrainment V Enantiospec. Deracemizat. Separate two enantiomers in solution: ° No diastereomeric salts formation ° No column chromatography 29 29 2. Enantiospecific/diasteriomeric resolution Variables: S enantiomer of API Entrainment R enantiomer of API V Enantiospec. Enantiopure chiral acid (coformer) Deracemizat. Solvent Temperature 5 variables !!! 30 30 2. Enantiospecific/diasteriomeric resolution For a fixed temperature Variables: S enantiomer of API R enantiomer of API Entrainment Chiral acid (coformer) V Enantiospec. Solvent Deracemizat. Temperature 4 variables ! Cocrystal RS-API 31 31 2. Enantiospecific/diasteriomeric resolution For a fixed temperature Solvent Entrainment R-API S-API + liq. + liq. V Enantiospec. RS-API Deracemizat. + liq. R-API + S-API + RS-API + RS-API + liq. liq. R-API RS-API S-API At racemic composition Cocrystal both enantiomers of API crystallize in the same crystal lattice RS-API 32 32 2. Enantiospecific/diasteriomeric resolution Solvent Entrainment S-cof. Enantiospec. S-API V + liq. + liq. CC + Deracemizat. liq. CC + S-API S-cof. + CC + liq. + liq. S-API Cocrystal S-coformer Cocrystal Cocrystal formation of S-API and S-coformer RS-API 33 33 2. Enantiospecific/diasteriomeric resolution Variables: S enantiomer of API R enantiomer of API Chiral acid (coformer) Entrainment Solvent V Enantiospec. Temperature Deracemizat. 4 variables ! Cocrystal RS-API 34 34 2. Enantiospecific/diasteriomeric resolution For a fixed temperature and Solvent a fixed molar% of solvent Variables: Entrainment S enantiomer of API S-coformer V Enantiospec. R enantiomer of API Deracemizat. Chiral acid (coformer) Solvent Temperature R- S-coformer API S-API 3 variables R- API 35 35S-API 2. Enantiospecific/diasteriomeric resolution Conditions for an effective chiral resolution: 1. Enantiospecific cocrystallization between one enantiomer Entrainment of an API and a chiral coformer in solution. V Enantiospec. Deracemizat. S-coformer S-coformer S-coformer + cocrystal Liq. Cocrystal RS-API cocrystal + RS-API R-API RS-API S-API 36 36 2. Enantiospecific/diasteriomeric resolution Conditions for an effective chiral resolution: 1. Enantiospecific cocrystallization between one enantiomer of an API and a chiral coformer in solution. 2. Area in which cocrystal solid phase is stable in suspension Entrainment need to cross the racemic composition line. V Enantiospec. Deracemizat. S-coformer S-coformer S-coformer + cocrystal Liq. Cocrystal RS-API cocrystal + RS-API 37 R-API RS-API S-API 37 2. Enantiospecific/diasteriomeric resolution I. S-2 II. LSMA co-crystal RS-1 S-2 At 9°C II+IV. + LSMA At -10°C Entrainment I+II. S-2 + LSMA V Enantiospec. Deracemizat. Liquid IV. RS-1 IV+V. RS-1 + R-1 R-2 S-1 Phase diagram of Etiracetam – Phase diagram of Etiracetam – S-mandelic acid in 89%mol of S-mandelic acid in 89%mol of acetonitril at 9°C acetonitril at -10°C Etiracetam – S-mandelic acid in acetonitrile 38 38 2. Enantiospecific/diasteriomeric resolution Diagram at crystallization temperature Seeding T until complete Solvent dissolution T to cyst. Temp. Entrainment Racemic compound V Enantiospec. Deracemizat. Chiral coformer Filtration and Cocrystal of onewashing enantiomer Mother liquor enriched and coformer in one enantiomer 100% ee Chiral resolution through enantiospecific co-crystallization in solution High yield (83% ) in a single resolution step with 100% of ee Works on compounds which do not or not easily form salts !!! 39 39 DE-racemization 40 3. Deracemization AND BEYOND???? Entrainment Enantiospec. V Deracemizat. MeOH, MeONa 41 3. Deracemization Entrainment Enantiospec. V Deracemizat. 42 3. Deracemization Chirality Resolution V Deracem. 96% ee, 34% yield 43 *B. Harmsen, Cryst. Growth Des., 2018 , 18, 441-448.
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]
  • Enantioselective Synthesis of the (1S,5R)-Enantiomer of Litseaverticillols a and B
    Biosci. Biotechnol. Biochem., 70 (10), 2564–2566, 2006 Note Enantioselective Synthesis of the (1S,5R)-Enantiomer of Litseaverticillols A and B y Akira MORITA, Hiromasa KIYOTA, and Shigefumi KUWAHARA Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan Received May 8, 2006; Accepted May 31, 2006; Online Publication, October 7, 2006 [doi:10.1271/bbb.60253] An enantioselective synthesis of the (1S,5R)-enan- which have recently culminated in the first enantiose- tiomer of litseaverticillols A and B was accomplished in lective total synthesis of (1R,5S)-(À)-1 and (1R,5S)-(À)- line with our previously reported synthetic pathway for 2.4) In this note, we describe the synthesis of their their (1R,5S)-enantiomer. The use of ‘‘EtSCeCl2’’ pre- enantiomers directed toward an evaluation of the differ- pared from EtSLi and CeCl3, instead of previously ence in biological activity between the enantiomers of employed EtSLi itself, for the formation of thiol ester litseaverticillols A and B. intermediates prevented any undesirable epimerization Our synthesis of (1S,5R)-1 and (1S,5R)-2 basically occurring in the process. followed our previous synthesis of their corresponding enantiomers, (1R,5S)-1 and (1R,5S)-2, respectively,4) Key words: litseaverticillol; enantioselective synthesis; except that (R)-4-benzyloxazolidin-2-one was employed sesquiterpenoid; anti-HIV as the source of chirality, instead of its (S)-form used in the previous synthesis. Homogeranic
    [Show full text]
  • Lecture 3: Stereochemistry and Drugs Key Objectives: 1
    Lecture 3: Stereochemistry and drugs Key objectives: 1. Be able to explain the role of stereochemistry in drug action or metabolism 2. Be able to identify a chiral center (or centers) in a drug 3. Be able to explain the difference between enantiomers and diastereomers Value of chirality and stereochemistry: Chirality as expressed through stereoisomers increases the specificity of molecule recognition and signaling. Like a key in a lock, or a hand in a glove. Some useful definitions: Chirality (and chiral centers): An object (such as a molecule) that is asymmetric and therefore not superimposable on its own image. Chiral centers are the most common features within molecules that give rise to chirality. Stereoisomer: A molecule that possesses at least one chiral center (or center of chirality). Enantiomers: A type of stereoisomer that exists in mirror image forms. See Figure 1. Diastereomers: A type of stereoisomer that possesses more than one chiral center. Stereospecific: A term used to describe a stereochemical property that one isomer possesses but the other does not. For example, the stereospecific metabolism of the S-enantiomer of a compound by an enzyme but the R-enantiomer is not metabolized by that enzyme. Stereoselective: A term used to describe a stereochemical property that is shared by both stereoisomers, but the property is greater in one isomer than the other. For example, the stereoselective binding of the R-enantiomer for a receptor indicates that the S-enantiomer also binds but not as avidly as the R-enantiomer. Enantiomers Figure 1: For enantiomers, many times we use the example of our left and right hands to demonstrate their asymmetry.
    [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]
  • Diastereomers Diastereomers
    Diastereomers Diastereomers: Stereoisomers that are not mirror images. enantiomer (R) (S) (S) (R) diastereomers diastereomer diastereomer enantiomer (R) (S) (R) (S) Diastereomers Diastereomers: Stereoisomers that are not mirror images. (R) enantiomer (S) (S) (R) diastereomer To draw the enantiomer of a molecule with chiral centers, invert stereochemistry at all chiral centers. (R) To draw a diastereomer of a molecule (R) with chiral centers, invert stereochemistry at only some chiral centers. Meso Compounds Meso: A molecule that contains chiral centers, but is achiral. 3 Are these molecules chiral? (R) (S) (These are diff eren t f rom th e 3 molecules I just showed; they have 2 -Cl’s, rather than 1 -Cl & 1 -OH. enantiomer (R) (S) (R) (S) These molecules are chiral mirror images of one another. (R,R) and (S,S) are not the same. Meso Compounds Meso: A molecule that contains chiral centers, but is achiral. 3 enantiomer ? (R) (S) (S) (R) no! 3 same molecule! enantiomer (R) (S) (R) (S) Meso Compounds Meso: A molecule that contains chiral centers, but is achiral. 3 enantiomer ? (R) (S) (S) (R) no! 3 same molecule! If a molecule • contains the same number of (R) and (S) stereocenters, and • those stereocenters have identical groups attached, then the molecule is achiral and meso. Meso Compounds Meso: A molecule that contains chiral centers, but is achiral. 3 same molecule (R) (S) (S) (R) 3 meso diastereomers meso diastereomer diastereomer enantiomer (R) (S) (R) (S) chiral chiral Properties of Enantiomers Most physical properties of enantiomers are identical. diethyl-(R,R)-tartrate diethyl-(S,S)-tartrate boiling point 280 °C 280 °C melting point 19 °C 19 °C density 1.204 g/mL 1.204 g/mL refractive index 1.447 1.447 i.e., chirality does not affect most physical properties.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [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]
  • 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.
    [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]
  • 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]