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Development of the Conjugate Addition/Nitro-Mannich Reaction

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Development of the conjugate addition/Nitro-Mannich reaction A Thesis presented by Andreas Kalogirou In Part Fulfilment of the requirement for the degree of Doctor of Philosophy University College London January 2013 UCL Chemistry Department 20 Gordon Street London WC1H 0AJ Andreas Kalogirou I, Andreas Kalogirou confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed………………………………………………………… Date…………………………………………………………… University College London 2 Andreas Kalogirou Abstract This thesis describes the development of the conjugate addition/nitro-Mannich reaction and its use in the synthesis of useful molecules like pyrrolidin-2-ones and piperazin-2-ones. The introductory chapter of this thesis outlines the literature related to the nitro-Mannich reaction, describing the different existing methodologies for performing the reaction in diastereo- and enantioselective manner. The synthetic applications of the reaction are also described, especially its uses in the synthesis of biologically active natural products. Moreover, the syntheses and uses of two classes of compounds, pyrrolidin-2-ones and piperazin-2-ones are briefly discussed. The results and discussion chapter starts by presenting the use of a one-pot conjugate addition/nitro-Mannich/lactamisation reaction in the synthesis of densely functionalised pyrrolidin-2-ones. The development of an asymmetric protocol, as well as some functionalisations of the pyrrolidinone core are also described. Our efforts to synthesise human neutrophil elastase inhibitor GW311616A using the developed methodology are then detailed. The next part of the results and discussion chapter portrays the development of a conjugate addition/nitro-Mannich reaction of non-zinc nucleophiles to ethyl 3- nitroacrylate and β-nitrostyrene. The scope and limitations of the reaction were investigated using a variety of different nucleophiles including amines, thiols, phosphines, alcohols, enolates and nitriles. Finally, our work towards synthesising the biologically active piperazin-2-one piperazirum, using the nitro-Mannich methodology is described. The diastereoselective synthesis and characterisation of a densely functionalised piperazin- 2-one was accomplished. A detailed description of the experimental details and analytical data for all novel compounds is described in the experimental section. Tables of coupling constants and X-ray crystallographic data are presented in the appendices section, followed by a list of literature references. University College London 3 Andreas Kalogirou Acknowledgements First of all I would like to thank my supervisor, Prof. Jim Anderson for giving me the opportunity to work in this very interesting subject and for his constant guidance and constructive criticism. I thank him for giving me valuable knowledge in chemistry during our weekly group meetings and our discussions. I would like to thank UCL’s technical staff for their help, especially Dr Abil Aliev and Dr Lisa Harrys. I would also like to thank Dr Graham J. Tizzard at the National Crystallography Service in Southampton for obtaining the X-ray crystal structures presented in this thesis. I would also like to thank Prof. Willie Motherwell for his inspiring discussions. Moreover, I am grateful to all the past and present members of the Anderson group for their help and support. I would like to give special thanks to Gyӧrgy, Rafa, Helen, Paul and Emily for their stimulating discussions and valuable suggestions that were important in developing this thesis. A big thanks goes to my parents for their financial support, without which this thesis would not be possible, as well as their constant encouragement and support. I also thank the “Cyprus State Scholarship Foundation” for their funding which was also important for my studies. I would like to thank my sister Anna for her help. Living in a foreign country is not easy and is made easier by having a member of the family nearby. Finally I would like to thank my friends Gyӧrgy and Aline for all their help and moral support. Without them life in London would not have been as colourful. University College London 4 Andreas Kalogirou Abbreviations ABCN 1,1'-Azobis(cyclohexanecarbonitrile) Ac Acetyl AIBN Azobisisobutyronitrile atm Atmospheres B Base BINOL 1,1’-Bi(2-naphthol) Bn Benzyl Boc tert-Butoxycarbonyl BOX Bisoxazoline Bu Butyl CAN Ceric(IV) ammonium nitrate Cbz Carboxybenzyl Cy Cyclohexyl DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC N,N'-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM Dichloromethane DMAP 4-(Dimethylamino)pyridine DMF Dimethylformamide DMSO Dimethylsulfoxide dr Diastereomeric ratio ee Enantiomeric excess E Electrophile Et Ethyl equiv. Equivalents University College London 5 Andreas Kalogirou DIPEA Diisopropylethylamine DIBAL Diisobutylaluminium hydride EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride h Hours Het Heterocycle HMBC Heteronuclear multiple-bond correlation spectroscopy HPLC High performance liquid chromatography HSQC Heteronuclear Single Quantum Coherence Hz Hertz iBu Isobutyl iPr Isopropyl IR Infrared J Coupling constant LG Leaving group Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes MOM Methoxymethyl ether MPTsOH II polymer-bound acid resin MS Molecular sieves NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect NOESY Nuclear Overhauser effect spectroscopy Nu Nucleophile OMB ortho-Methoxybenzyl University College London 6 Andreas Kalogirou OMP ortho-Methoxyphenyl P Protecting group Ph Phenyl PMB para-Methoxybenzyl PMP para-Methoxyphenyl ppm Parts per million Pr Propyl pTSA para-Toluenesulfonic acid rt Room temperature sm Starting material SN2 Bimolecular nucleophilic substitution TBAF Tetra-nbutylammonium fluoride TBDMS tert-Butyldimethylsilyl tBu tert-Butyl Tf Triflate TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin Layer Chromatography TMS Trimethylsilyl TMSCl Trimethylsilyl chloride Tol para-Tolyl LDA Lithium diisopropylamide Å Angstrom oC Degrees Centigrade University College London 7 Andreas Kalogirou Table of Contents Page Abstract 3 Acknowledgements 4 Abbreviations 5 Table of Contents 8 1. Introduction 13 1.1 The nitro-Mannich reaction 13 1.1.1 Overview 13 1.1.2 Initial development 14 1.1.3 Non-catalytic nitro-Mannich reactions 15 1.1.4 Non-catalytic enantioselective nitro-Mannich reactions 16 1.1.5 Metal-catalysed nitro-Mannich reactions 17 1.1.6 Organocatalytic nitro-Mannich reactions 21 1.2 Stereoselective 1,4-addition to nitroalkenes 24 1.2.1 Substrate/auxiliary controlled 1,4-Additions 24 1.2.2 Metal-catalysed 1,4-Additions 26 1.2.3 1,4-Additions of Oxygen nucleophiles 28 1.2.4 1,4-Additions of Nitrogen nucleophiles 30 1.2.5 Miscellaneous 1,4-Additions 32 1.2.6 Summary 34 1.3 Synthetic applications of the nitro-Mannich reaction 35 1.3.1 Functional group modifications-Nitro group reduction 35 1.3.2 Functional group modifications-Nef reaction 36 1.3.3 Functional group modifications-Denitration 38 1.3.4 Synthesis of natural products 39 1.4 Stereoselective synthesis of piperazinones 41 University College London 8 Andreas Kalogirou 1.4.1 Vicinal diamines 42 1.4.2 Biologically important piperazin-2-ones 42 1.4.3 Synthesis of piperazin-2-ones 44 1.5 Stereoselective syntheses of pyrrolidinones 47 2. Results and discussion 52 2.1 Previous work and methodology 52 2.2 Proposed research 55 2.3 Stereoselective synthesis of pyrrolidinones via Nitro-Mannich reaction 57 2.3.1 Synthesis of starting materials 57 2.3.2 Expansion of the reaction scope 59 2.3.3 Use of other dialkylzinc reagents 63 2.3.4 Superhydride® as a nucleophile 64 2.3.5 Tandem reaction 66 2.3.6 Relative Stereochemistry 67 2.3.7 Origin of diastereoselectivity 68 2.3.8 Asymmetric methodology 70 2.3.9 Further functionalisation of the parent pyrrolidinone 75 2.3.9.1 Nef reaction 75 2.3.9.2 Reactions of pyrrolidinone 233 with electrophiles 77 2.3.9.3 Denitration 80 2.3.9.4 Modification of the C5 substituent, acetal hydrolysis 81 2.3.9.5 Modification of the C5 substituent, synthesis of proline analogue 319 82 2.3.10 Conclusions 84 2.3.11 Future work 86 2.4 Towards the synthesis of a human neutrophil elastase inhibitor (GW311616A) 87 University College London 9 Andreas Kalogirou 2.4.1 Precedence and methodology 87 2.4.2 Investigation of the synthesis 89 2.4.3 Conclusions 96 2.4.4 Future work 97 2.5 The 1,4-addition/Nitro-Mannich reaction of non-zinc nucleophiles on β-nitrostyrene 97 2.5.1 Precedence and methodology 97 2.5.2 Investigation of 1,4-addition reactions to nitroacrylate 231 98 2.5.2.1 Carbon nucleophiles 98 2.5.2.2 Oxygen nucleophiles 100 2.5.2.3 Nitrogen nucleophiles 103 2.5.2.4 Other nucleophiles 105 2.5.3 Nitro-Mannich reactions of 1,4-addition products of 231 106 2.5.3.1 One pot reactions 106 2.5.3.2 Two pot reactions 109 2.5.3.3 Relative stereochemistry 111 2.5.3.4 Source of diastereoselectivity 113 2.5.4 Investigation of 1,4-addition reactions to β-nitrostyrene 380 114 2.5.4.1 Carbon nucleophiles 114 2.5.4.2 Oxygen nucleophiles 115 2.5.4.3 Nitrogen nucleophiles 118 2.5.4.4 Other nucleophiles 119 2.5.5 Nitro-Mannich reactions of 1,4-addition products of β-nitrostyrene 119 2.5.5.1 Adducts of carbon nucleophiles 120 2.5.5.2 Adducts of oxygen nucleophiles 122 2.5.5.3 Adducts of nitrogen nucleophiles 125 University College London 10 Andreas Kalogirou 2.5.5.4 Adducts of other nucleophiles 127 2.5.6 Relative stereochemistry 128 2.5.6.1 Carbon adducts 131 2.5.6.2 Oxygen adducts 134 2.5.6.3 Nitrogen adducts 135 2.5.6.4 Sulfur adducts 138 2.5.7 Source of diastereoselectivity 141 2.5.8 Conclusions 148 2.5.9 Future work 149 2.6 The synthesis of Piperazirum via the Nitro-Mannich methodology 150 2.6.1 Isolation 150 2.6.2 Strategy 151 2.6.3 Synthesis 152 2.6.4 Relative stereochemistry 157 2.6.5 Comparison to natural compound 161 2.6.6 Synthesis of other analogues 162 2.6.7 Conclusions and future work 165 3.
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  • Approach and Synthesis of Strychnos Alkaloids

    Approach and Synthesis of Strychnos Alkaloids

    N° d'ordre : 4155 THÈSE Présentée à L'UNIVERSITÉ BORDEAUX I ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES par Dawood Hosni DAWOOD POUR OBTENIR LE GRADE DE DOCTEUR SPÉCIALITÉ : CHIMIE ORGANIQUE ********************* TOWARDS THE SYNTHESIS OF MONOTERPENOIDS INDOLE ALKALOIDS OF THE ASPIDOSPERMATAN AND STRYCHNAN TYPE ********************* Soutenue le: 17 décembre 2010 Après avis de: MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur Devant la commission d'examen formée de : MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur POISSON Jean-François Chargé de recherche, CNRS Examinateur VINCENT Jean-Marc Directeur de recherche, CNRS Examinateur LANDAIS Yannick Professeur, Bordeaux 1 Directeur de thèse ROBERT Frédéric Chargé de recherche, CNRS Codirecteur de thèse - 2010 - Abbreviations ∆: reflux °C: celsius degrees Ac: acetyle ALB Aluminium Lithium bis(binaphthoxide) complex AIBN : azobis(isobutyronitrile) aq.: aqueous Ar : aromatic BINAP : 2,2'-bis(diphenylphosphino)-1,1'-binaphthyle BINAPO : 2-diphenylphosphino-2'-diphenylphosphinyl-1,1'-binaphthalene BINOL: 1,1’-bi-2-naphthol Boc: tert-butyloxycarbonyle BOX: Bisoxazoline Bz : benzoyle Bn: benzyle cat. : catalytic DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCC: dicyclohexacarbodiimide dr.: diastereomeric ratio DIBAL-H: diisobutylaluminium hydride DIPEA: diisopropyléthylamine (Hünig Base) DMAP: dimethylaminopyridine DME: dimethoxyethane