DOCSLIB.ORG

Asymmetric Catalysis: Ligand Design and Conformational Studies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Asymmetric Catalysis: Ligand Design and Conformational Studies _____________________________ Asymmetric Catalysis: Ligand Design and Conformational Studies Kristina Hallman Stockholm 2001 Royal Institute of Technology Department of Chemistry Organic Chemistry ______________________________ Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av filosofie doktorsexamen i organisk kemi, fredagen den 14:e december, 2001, kl 13.00 i Kollegiesalen, Administrationsbyggnaden, KTH, Valhallavägen 79, Stockholm. Avhandlingen försvaras på engelska. ISBN: 91-7283-200-2 ISRN KTH/IOK/FR—01/67-SE ISSN 1100-7974 TRITA-IOK Forskningsrapport 2001:67 Kristina Hallman, Stockholm 2001 Tryck: Nykopia Global Print AB, Stockholm 2001 Hallman, Kristina; Asymmetric Catalysis: Ligand Design and Conformational Studies. Royal Institute of Technology, Stockholm, December 2001 Abstract This thesis deals with the design of ligands for efficient asymmetric catalysis and studies of the conformation of the ligands in the catalytically active complexes. All ligands developed contain chiral oxazoline heterocycles. The conformations of hydroxy- and methoxy-substituted pyridinooxazolines and bis(oxazolines) during Pd-catalysed allylic alkylations were investigated using crystallography, 2D-NMR techniques and DFT calculations. A stabilising OH-Pd interaction was discovered which might explain the difference in reactivity between the hydroxy- and methoxy-containing ligands. The conformational change in the ligands due to this interaction may explain the different selectivities observed in the catalytic reaction. Polymer-bound pyridinooxazolines and bis(oxazolines) were synthesised and employed in Pd-catalysed allylic alkylations with results similar to those of monomeric analogues; enantioselectivities up to 95% were obtained. One polymer-bound ligand could be re-used several times after removal of Pd(0). The polymer-bound bis(oxazoline) was also used in Zn-catalysed Diels-Alder reactions, but the heterogenised catalyst gave lower selectivities than a monomeric analogue. A series of chiral dendron-containing pyridinooxazolines and bis(oxazolines) were synthesised and evaluated in Pd-catalysed allylic alkylations. The dendrons did not seem to have any influence on the selectivity and little influence on the yield when introduced in the pyridinooxazoline ligands. In the bis(oxazoline) series lower generation dendrimers had a postive on the selectivity, but the selectivity and the activity decreased with increasing generation. Crown ether-containing ligands were investigated in palladium-catalysed alkylations. No evidence of a possible interaction between the metal in the crown ether and the nucleophile was discovered. A new type of catalyst, an oxazoline-containing palladacycle was found to be very active in oxidations of secondary alcohols to the corresponding aldehydes or ketones. The reactions were performed with air as the re-oxidant. Therefore, this is an enviromentally friendly oxidation method. Keywords: asymmetric catalysis, chiral ligand, oxazolines, conformational study, allylic substitution, polymer-bound ligands, dendritic ligands, crown ether, oxidations, palladacycle. Table of Contents Abstract List of Publications Abbrevations 1. Introduction 1 1.1 Asymmetric Catalysis 1 1.2 Allylic Alkylation 2 1.2.1 Background 2 1.2.2 Mechanism 3 1.3 Aim of the Study 7 2. Ligand Influence on the Asymmetric Induction 8 2.1 Background 8 2.2 Conformational Studies upon Steric Effects 12 2.2.1 Pyridyl Alcohol Ligands 12 2.2.2 Bis(oxazoline) Ligands 21 2.3 Electronic Effects 25 3. Polymer-Bound Ligands in Asymmetric Catalysis 27 3.1 Background 27 3.2 Polymer-Bound Pyridinooxazolines 29 3.2.1 Synthesis 29 3.2.2 Evaluation in the Allylic Alkylation 31 3.3 Polymer-Bound Bis(oxazoline) Ligands 32 3.3.1 Background 32 3.3.2 Synthesis 34 3.3.3 Evaluation in the Allylic Alkylation 34 3.3.4 Evaluation in the Diels-Alder Reaction 35 4. Dendrimers and Dendrons in Asymmetric Catalysis 38 4.1 Background 38 4.2 Synthesis and Evaluation in the Allylic Alkylation 43 5. Asymmetric Catalysis using Crown Ethers as Ligands 47 5.1 Background 47 5.2 Synthesis of Ligands and Evaluation of Rate Enhancement In the Allylic Alkylation 47 6. Palladium-Catalysed Oxidations using Air as Reoxidant 50 6.1 Background 50 6.2 Evaluation of the Catalyst 50 7. Concluding Remarks 53 Acknowledgments 54 List of Publications I. (Hydroxyalkyl)pyridinooxazolines in Palladium-Catalyzed Allylic Substitutions. Conformational Preferences of the Ligand Svensson, M.; Bremberg, U.; Hallman, K.; Csöregh, I.; Moberg, C. Organometallics, 1999, 18, 4900. II. OH-Pd(0) Interaction as a Stabilizing Factor in Palladium Catalyzed Allylic Alkylations Hallman, K.; Svensson, M.; Moberg, C. Manuscript. III. Enantioselective allylic alkylation using polymer-supported palladium catalysts Hallman, K.; Macedo, E.; Nordström, K.; Moberg, C. Tetrahedron: Asymmetry 1999, 10, 4037. IV. Polymer-bound bis(oxazoline) as a chiral catalyst Hallman, K.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 1475. V. Dendritic Oxazoline Ligands in Enantioselective Palladium-Catalyzed Allylic Alkylations Hallman, K.; Malkoch, M.; Lutsenko, S.; Malmström, E.; Hult, A.; Moberg, C. Manuscript. VI. Chiral Ditopic Receptors Application to Palladium-Catalyzed Allylic Alkylation Bourguignon, J.; Bremberg, U.; Dupas, G.; Hallman, K.; Hortala, L.; Levacher, V.; Lutsenko, S.; Macedo, E.; Moberg, C.; Quéguiner, G.; Rahm, F. Manuscript. VII. Palldium(II)-Catalyzed Oxidation of Alcohols with Air as Reoxidant Hallman, K.; Moberg, C. Adv. Synth. Catal. 2001, 343, 260. The published papers were reprinted with kind permission from WILEY-VCH Verlag GmbH, Pappelallee, 3D-69469 Weinheim, Germany; The American Chemical Society, 1155 Sixteenth Street, N. W., Washington, DC 20036, USA and Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington, OX5 1GB, UK. Abbreviations BINAP 2,2-Bis(diphenylphosphanyl)-1,1'-binaphtyl BINOL 1,1'-Bi(2-naphthol) B3LYP A hybrid density functional method BSA N,O-Bis(trimethylsilyl)acetamide COSYgs Correlation spectroscopy, gradient spectroscopy; a 2D-NMR method that is used to detect heteronuclear couplings DCC N,N-Dicyclohexylcarbodiimide DDB 2,3-Dimethoxy-1,4-bis(dimethylamino)butane DEAD Diethyl azodicarboxylate DIOP 1,4-Bis(diphenylphosphino)-1,4-dideoxy-2,3-O-isopropylidene- threitol DiPAMP 1,2-Bis[(o-methoxy)phenylphosphino]ethane DFT Density Functional Theory DMAP 4-(Dimethylamino)pyridine DPCM A method used to calculate solvent effects dppf 1,1'-Bis(diphenylphosphino)ferrocene DPTS 4-(Dimethylamino)pyridinium-4-toluenesulfonate EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HMQCgs Heteronuclear multiple quantum coherence, gradient spectrsocopy; a 2D-NMR method that is used to detect homonuclear couplings lacvp* A basis set used in DFT calculations NOSEY Nuclear Overhauser effect spectroscopy PEG Poly(ethylene glycol) PS Polystyrene rac Racemate 1 Introduction 1.1 Asymmetric Catalysis The need for enantiopure compounds is increasing since the pharmaceutical industry today has limited use for racemates. The technique that still is the most popular for furnishing enantiopure material is resolution of racemates, despite the fact that the yield of the desired enantiomer is at best 50% using traditional methods. If the undesired enantiomer cannot be racemised and recycled it will also give rise to a waste problem. The use of chiral auxiliaries gives rise to the same problem; a lot of waste is generated if the auxiliary can not be reused. Since enantiopure starting materials from the chiral pool are not always available (particularly on a large scale), an attractive alternative method is enantioselective catalysis. There are basically two kinds of catalysts that can be used, biocatalysts and chiral synthetic catalysts. Why industry today, 30 years after the discovery of asymmetric catalysis, still uses “old-fashioned” methods may be due to several reasons. The price of the metal and the chiral catalyst along with the difficulties associated with the recycling and separation of the catalyst are maybe the most important factors. Nature is an expert in the synthesis of enantiopure compounds; the technique used is enzymatic enantioselective catalysis. Many scientists have, since the end of the sixties, tried to mimic the enantioselective processes mediated by enzymes and to achieve this, a plethora of chiral ligands have been developed. Some of these systems have levels of activity and selectivity approaching those of an enzyme. Several catalytic reactions have been developed allowing enantioselective formation of C-H, C-C, C-O, C-N, and other bonds, often with excellent results in terms of efficiency and selectivity. The two most important aspects of a new catalyst are its ability to increase reaction rate and improve enantioselectivity. This can be achieved via appropriate molecular architecture of the catalyst and optimised reaction conditions. In the design of a new, successful catalyst, the steric and electronic properties of the ligand as well as the nature of the metal are important. The metals used are usually transition metals. The ideal ligand should be easily accessible and the ligand- structure should be labile to systematic modification, allowing optimisation for participation in a specific application. 1 The aim of this introduction is to provide a background to the chemistry described in this thesis and not to give a review. There are several excellent reviews on this area. 1 1.2 Allylic Alkylation
Load more

Recommended publications
  • From Synthetic Chemistry and Stereoselective Biotransformations
    PP Periodica Polytechnica From Synthetic Chemistry and Chemical Engineering Stereoselective Biotransformations to Enzyme Biochemistry – The Bioorganic Chemistry Group at the Budapest 59(1), pp. 59-71, 2015 University of Technology and Economics DOI: 10.3311/PPch.7390 Creative Commons Attribution b Zoltán BOROS1, Gábor HORNYÁNSZKY1, József NAGY1, László POPPE1 * research article Received 04 March 2014; accepted after revision 05 May 2014 Abstract 1 Introduction The activity of Bioorganic Chemistry Group (BCG) within 1.1 Scientific background of the Bioorganic Chemistry Department of Organic Chemistry and Technology at Budapest Research Group University of Technology and Economics is related to various The activity of Bioorganic Chemistry Group (BCG) of areas of synthetic chemistry, biotechnology and enzymology. Department of Organic Chemistry and Technology at Budapest This review gives an overview on the research activity of the University of Technology and Economics is related to various group covering development of synthetic organic chemistry areas of synthetic chemistry, selective biocatalysis [1] and methods; stereoselective biotransformations with lipases, enzymology with major emphasis on development of novel ammonia-lyases and further biocatalysts in batch and tools for stereoselective synthesis [2]. continuous-flow reactions; novel enzyme immobilization One of the main challenges facing organic chemistry is methods; and enzyme structural and mechanistic studies by the rational synthesis of an ever growing number of complex, experimental and computational techniques. optically active natural products and their analogues [3]. According to the regulation of FDA production of chiral Keywords drugs, agrochemicals, fine chemicals has been allowed in synthetic organic chemistry, stereoselective biotransformation, enantiomerically pure form, because it often happens that only continuous-flow reaction, lipase, ammonia-lyase, enzyme one of the two enantiomers shows the required therapeutical immobilization, enzyme structure, enzyme mechanism, QM/ effect [4].
    [Show full text]
  • 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.
    [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]
  • Page 1 of 108 RSC Advances
    RSC Advances This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 108 RSC Advances Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis Majid M. Heravi,* Vahideh Zadsirjan, Behnaz Farajpour Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran Email: [email protected] Abstract Various chiral oxazolidinones (Evans' oxazolidinones) have been employed as effective chiral auxiliaries in the asymmetric alkylation of different enolates. This strategy has been found promising and successful when used as key step (steps) in the total synthesis of several biologically active natural products. In this report, we try to underscore the applications of Manuscript oxazolidinones as chiral auxiliary in asymmetric alkylation, and particularly in crucial chiral inducing steps in the total synthesis of natural products, showing biological activities.
    [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]
  • Download Author Version (PDF)
    Chemical Science Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/chemicalscience Page 1 of 4 PleaseChemical do not adjust Science margins Chemical Science EDGE ARTICLE Absolute Structure Determination of Compounds with Axial and Planar Chirality Using the Crystalline Sponge Method a a a b a Received 00th January 20xx, Shota Yoshioka, Yasuhide Inokuma, Manabu Hoshino, Takashi Sato, and Makoto Fujita* Accepted 00th January 20xx The absolute stereochemistry of compounds with axial and planar chirality is successfully determined by the crystalline DOI: 10.1039/x0xx00000x sponge method without crystallization or derivatization of the compounds. This method is applied to absolute structure determination in the asymmetric synthesis of unique compounds with axial and planar chirality.
    [Show full text]
  • Synthesis of Axially Chiral Biaryl Compounds by Asymmetric Catalytic Reactions with Transition Metals Pauline Loxq, E
    Synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals Pauline Loxq, E. Manoury, Rinaldo Poli, Éric Deydier, A. Labande To cite this version: Pauline Loxq, E. Manoury, Rinaldo Poli, Éric Deydier, A. Labande. Synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals. Coordination Chemistry Re- views, Elsevier, 2016, 308, Part 2, pp.131-190. 10.1016/j.ccr.2015.07.006. hal-01929757 HAL Id: hal-01929757 https://hal.archives-ouvertes.fr/hal-01929757 Submitted on 1 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals Pauline Loxq, a,b Eric Manoury,a,b Rinaldo Poli,a,b,c Eric Deydier a,b,d,* and Agnès Labande a,b,* a CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France. b Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France. c Institut Universitaire de France, 103, bd Saint-Michel, 75005 Paris, France. d IUT A Paul Sabatier, Departement de Chimie, Avenue Georges Pompidou, CS 20258, F- 81104 Castres Cedex, France Dedicated to the memory of our colleague and friend Guy Lavigne (1947-2015).
    [Show full text]
  • Formation and Crystallization Based Separation of Diastereomeric Salts
    Formation and Crystallization based Separation of Diastereomeric Salts Der Fakultät für Verfahrens- und Systemtechnik der Otto-von-Guericke-Universität Magdeburg zur Erlangung des akademischen Grades Doktoringenieur (Dr.-Ing.) am: 03.05.2012. vorgelegte Dissertation (Einreichungsdatum) von: M.Sc. Venkata Subbarayudu Sistla i Schriftliche Erklärung Ich erkläre hiermit, dass ich die vorliegende Arbeit ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe. Die aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche kenntlich gemacht. Insbesondere habe ich nicht die Hilfe einer Kommerziellen Promotionsberatung in Anspruch genommen. Dritte haben von mir weder unmittelbar noch mittelbar geldwerte Leistungen für Arbeiten erhalten, die im Zusammenhang mit dem Inhalt der vorgelegten Dissertation stehen. Die Arbeit wurde bisher weder im Inland noch im Ausland in gleicher oder ähnlicher Form als Dissertation eingereicht und ist als Ganzes auch noch nicht veröffentlicht. (Magdeburg, 03.05.2012) (M.Sc. Venkata Subbarayudu, Sistla) ii It’s an immense pleasure for me to dedicate this work to my Uncle M.K. Ramatarakam garu and to my parents Sistla. Lakshmi Savitri Annapurna Devi and Sistla.Venkateswarlu. iii Acknowledgement First of all, I bow in front of the lord Sita-Rama, Who is there along with me all along in my life and made me to follow the path of truth in all the situations when my mind was not stable. I would like to convey my profound gratitude to Professor Andreas Seidel-Morgenstern and apl. Professor Heike Lorenz as they gave me this great opportunity to explore myself and in the area of Crystallization. I am proud to be in the group PCG under the guidance of Prof.
    [Show full text]
  • 1,2-Asymmetric Induction in Carbonyl Compounds - a Computational Study
    1,2-Asymmetric Induction in Carbonyl Compounds - A Computational Study by Jeffrey Retallick B.Sc., University of New Brunswick, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science In the Graduate Academic Unit of Chemistry Supervisor(s): Ghislain Deslongchamps, Ph.D., Chemistry Examining Board: Rodney Cooper, M.Sc., Computer Science, Chair External Examiner: Ben Newling, Ph.D., Physics This thesis is accepted by the Dean of Graduate Studies THE UNIVERSITY OF NEW BRUNSWICK October, 2019 © Jeffrey Retallick, 2020 Abstract In asymmetric synthesis, it is important to reliably predict the major stereoisomeric prod- uct of a reaction. One such reaction is the nucleophilic addition to a carbonyl compound featuring an adjacent chiral carbon. Several reaction models exist in literature to predict the facial selectivity of these reactions. These models provide simple visual drawings to quickly predict the major product of such a reaction without requiring exhaustive quantum mechanical calculations. These models are used on a daily basis, and some models per- form better than others, making it valuable to investigate which ones are the most effective. For the first time in this thesis, high-level computations have been performed on all of the literature models to verify their efficacy. The results of this thesis offers a definitive answer that the Felkin-Anh and Wintner models are the most effective, and that bent bond theory offers an interesting insight on the mechanics of these reactions. ii Dedication Kyle, Nan, and Taryn. iii Acknowledgements Thanks to my family for their support. Ghislain, thank you for putting up with me over the past while.
    [Show full text]
  • Chapter 8. Chiral Catalysts José M
    Chapter 8. Chiral Catalysts José M. Fraile, José I. García, José A. Mayoral 1. The Origin of Enantioselectivity in Catalytic Processes: the Nanoscale of Enantioselective Catalysis. Enantiomerically pure compounds are extremely important in fields such as medicine and pharmacy, nutrition, or materials with optical properties. Among the different methods to obtain enantiomerically pure compounds, asymmetric catalysis1 is probably the most interesting and challenging, in fact one single molecule of chiral catalyst can transfer its chiral information to thousands or even millions of new chiral molecules. Enantioselective reactions are the result of the competition between different possible diastereomeric reaction pathways, through diastereomeric transition states, when the prochiral substrate complexed to the chiral catalyst reacts with the corresponding reagent. The efficiency of the chirality transfer, measured as enantiomeric excess [% ee = (R−S)/(R+S) × 100], depends on electronic and steric factors in a very subtle form. A simple calculation shows that differences in energy of only 2 kcal/mol between these transition states are enough to obtain more than 90% ee, and small changes in any of the participants in the catalytic process can modify significantly this difference in energy. Those modifications may occur in the near environment of the catalytic centre, at less than 1 nm scale, but also at longer distances in the catalyst, substrate, reagent, solvent, or support in the case of immobilized catalysts. This is the reason because asymmetric
    [Show full text]
  • [2.2]Paracyclophane-Based Bisoxazoline Ligands and Their
    molecules Communication PlanarCommunication Chiral [2.2]Paracyclophane-Based Bisoxazoline LigandsPlanar Chiral and Their [2.2]Paracyclophane-Based Applications in Cu-Mediated Bisoxazoline N–H InsertionLigands and Reaction Their Applications in Cu-Mediated N–H Insertion1, Reaction1, 1 2 1,3, Daniel M. Knoll y , Yuling Hu y, Zahid Hassan , Martin Nieger and Stefan Bräse * 1 DanielInstitute M. ofKnoll Organic 1,†, Yuling Chemistry Hu (IOC),1,†, Zahid Karlsruhe Hassan Institute 1, Martin of Nieger Technology 2 and (KIT), Stefan Fritz-Haber-Weg Bräse 1,3,* 6, 76131 Karlsruhe, Germany; [email protected] (D.M.K.); [email protected] (Y.H.); 1 [email protected] Institute of Organic Chemistry (Z.H.) (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 2 DepartmentKarlsruhe, Germany; of Chemistry, [email protected] University of Helsinki, (D.M.K.); P.O. [email protected] Box 55 A.I. Virtasen aukio (Y.H.); 1, 00014 Helsinki, Finland; martin.nieger@helsinki.fi[email protected] (Z.H.) 2 3 Institute Department of Toxicology of Chemistry, and University Genetics (ITG), of Helsinki, Karlsruhe P.O. InstituteBox 55 A.I. of Virtasen Technology aukio (KIT), 1, 00014 Helsinki, Hermann-von-Helmholtz-PlatzFinland; [email protected] 1, D-76344 Eggenstein-Leopoldshafen, Germany 3 * Correspondence: Institute of Toxicology [email protected]; and Genetics Tel.: (ITG),+49-7216-084-2902 Karlsruhe Institute of Technology (KIT), Hermann-von- TheseHelmholtz-Platz authors contributed 1, D-76344 equally Eggenstein-Leopoldshafen, to this work. Germany. y * Correspondence: [email protected]; Tel.: +49-7216-084-2902 † These authors contributed equally to this work.
    [Show full text]
  • Kem-4.450 Asymmetric Synthesis
    KemKem--4.4504.450 AsymmetricAsymmetric SynthesisSynthesis Prof. Ari Koskinen Laboratory of Organic Chemistry © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 ChiralityChirality andand DifferingDiffering PropertiesProperties OO Carvone spearmint odor caraway NH NH 2 H 2 H Aspartame HO2C NCO2Me HO2C NCO2Me (Nutrasweet) O O sweet bitter O O Thalidomide N N O O OON OON H H sedative, hypnotic teratogenic © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Growing need for enantiopure compounds Enantiomers/diastereomers may have adverse effects Diastereomers usually easier to separate Enantiomers: FDA required © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Penicillamine: NH2 NH2 CO2H CO2H SH SH antidote for Pb, Au, Hg can cause optic atrophy => blindness Timolol: O OH O OH H H N O N N O N N N N N S S adrenergic blocker ineffective © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SalesSales ofof EnantiomericEnantiomeric DrugsDrugs andand IntermediatesIntermediates Chem. Eng. News 2001, 79 (40), 79-97. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 AsymmetricAsymmetric InductionInduction -- DefinitionsDefinitions Chirality - handedness Asymmetry - lacking all symmetry (except E) B Dissymmetry - lacking some element of symmery H NB!!! Molecules can be chiral but not asymmetric!
    [Show full text]