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Stereoselective Synthesis of Pyrrolidinones Via Nitro-Mannich Reaction

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Stereoselective Synthesis of Pyrrolidinones Via Nitro-Mannich Reaction Stereoselective Synthesis of Pyrrolidinones via Nitro-Mannich Reaction Towards the Synthesis of Popolohuanone E A Thesis Presented by Lisa Rebecca Horsfall In Part Fulfilment of the Requirement for the Degree of Doctor of Philosophy University College London April 2011 I, Lisa Rebecca Horsfall 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…………………………………………………………… 2 Abstract Part 1: The first section of this thesis details the stereoselective synthesis of pyrrolidinones via the nitro-Mannich reaction. Expanding on previous work within the Anderson group, conjugate addition of a diorganozinc species to nitroacrylate 141 was carried out successfully. Subsequent in situ nitro-Mannich reaction was then followed by spontaneous lactamisation to afford the desired five-membered ring pyrrolidinone structure. The reaction was performed in one pot, generating three contiguous stereocentres in a highly diastereoselective manner. The scope of the reaction was investigated by varying substituents on the imine partner. This led to the synthesis of a broad range of analogues incorporating alkyl, aryl and heteroaryl functional groups, each isolated as a single diastereoisomer in 48-84% yield. Studies to develop an asymmetric variant of the reaction were performed, with Feringa’s phosphoramidite ligand 299 enabling formation of the pyrrolidinone with a moderate 52% e.e. Analysis of the reaction mechanism and the origin of the observed diastereoselectivity have been investigated, followed by further functionalisation of the pyrrolidinone structure to yield a wide range of synthetically useful building blocks. Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. J. Org. Chem. 2011 , 76 , 1961 (featured article). Part 2: This section describes work towards the total synthesis of popolohuanone E (1), a marine natural product isolated from the Dysidea sp. sponge in 1990. The molecule contains a unique trihydroxylated dibenzofuran-1,4-dione core and two identical sesquiterpene units. The complex molecular structure and interesting biological activity of popolohuanone E ( 1) has made this compound a particularly interesting target. Synthesis of model system 132 was successfully achieved, which allowed investigations into the key oxidative dimerisation reaction. Extensive studies led to isolation of the desired bis-quinone 133 in 40% yield, followed by acid catalysed cyclisation to form the dibenzofuran core present in popolohuanone E ( 1), in 26% yield. Focus then turned to the synthesis of the proposed precursor to popolohuanone E ( 1), 6’-hydroxyarenarol (7), based on the route developed within the Anderson group. Studies began with the enantioselective synthesis of intermediate iodide 83 3 utilising Myers’ pseudo -ephedrine auxillary. The remaining stereocentres were subsequently installed via an intramolecular Hosomi-Sakurai reaction in high yield and diastereoselectivity. With the cis -decalin framework in hand, construction of the phenolic portion was achieved by addition of lithiated 1,2,4-trimethoxybenzene to neo -pentyl aldehyde 74 , followed by deoxygenation using Barton-McCombie conditions. Installation of the exo -cyclic alkene, followed by removal of the three methyl ether protecting groups, then afforded the required precursor 6’- hydroxyarenarol ( 7). Finally, dimerisation was attempted as developed previously on model system 132 , however none of the desired bis-quinone ( 18 ) was observed. 4 Acknowledgements I would firstly like to thank my supervisor Prof. Jim Anderson. He has allowed me to study two extremely interesting and challenging projects and has given me constant support and encouragement throughout my Ph.D. We have had many thought provoking discussions and I thank him for allowing me to develop my own research, with guidance and enthusiasm. I would like to thank the technical staff at the University of Nottingham and University College London. In particular, the stores staff and Mr Dane Toplis at The University of Nottingham and Dr. Abil Aliev and Dr. Lisa Harris at University College London have been invaluble during my studies. I would also like to thank both The University of Nottingham and University College London for funding, without which my Ph.D could not have been conducted. In addition I am very greatful to the past and present members of the Anderson group, particularly those who enjoyed the move to London. These people have provided a fantastic working atmosphere, with many stimulating discussions, much enthusiasm and of course frequent social events. Finally I would like to thank my family and friends, who have constantly supported me over the last three and a half years. I would particularly like to thank my Dad, Mum and my sister Claire for their encouragement and support. Special thanks go to Lynnie and Richard for putting a roof over my head and my partner Rich, who has done more than he knows. It is to these people that I dedicate this thesis. 5 Abbreviations Å angstrom(s) AIBN azobis(isobutyronitrile) Anal. analytical app. apparent aq. aqueous Ar aryl Boc tert-butyloxycarbonyl BINOL 1,1'-bi-2-naphthol Bn benzyl BOX bisoxazoline br broad BSA bis(trimethylsilyl)acetamide Bu butyl Calcd. calculated CAN ceric ammonium nitrate CBS Corey-Bakshi-Shibata CI + positive ion chemical ionisation COD cyclooctadiene COSY correlation spectroscopy Cq quaternary carbon CSA camphorsulfonic acid Cy cyclohexyl δ chemical shift d doublet DBU 1,8-diazabicycloundec-7-ene DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DEPT distortionless enhancement by polarisation transfer DIBAL diisobutylaluminium hydride DIPEA diisopropylethylamine DMF N,N-dimethylformamide DMS dimethylsulfide DNA deoxyribonucleic acid 6 d.r. diastereomeric ratio DTBP 4,4’-di-tert -butylbiphenyl e.e. enantiomeric excess EI + positive ion electron impact equiv. equivalent(s) e.r. enantiomeric ratio ES + positive ion electron spray ESR electron spin resonance Et ethyl Et 3N triethylamine Et 2O diethyl ether g gram(s) GABA γ-aminobutyric acid h hour(s) HMBC heteronuclear multiple bond coherence HMPA hexamethylphosphoramide HMQC heteronuclear multiple quantum coherence HOMO highest occupied molecular orbital HPLC high performance liquid chromatography HRMS high resolution mass spectrometry IC 50 half maximal inhibitory concentration Imid imidazole IR infra-red J coupling constant KHMDS potassium bis(trimethylsilyl)amide LB Lewis base LDA lithiumdiisopropylamide Lit. literature LUMO lowest unoccupied molecular orbital M moles per litre m multiplet M+ molecular ion m meta 7 MBH Mortia-Baylis-Hillman m-CPBA meta -chloroperoxybenzoic acid Me methyl mg milligram(s) MHz megahertz min minute(s) mL millilitre(s) mmol millimole(s) mol mole(s) MOM methoxymethyl ether mp. melting point MS molecular sieves n normal NaHMDS sodium bis(trimethylsilyl)amide n-BuLi normal-butyllithium NCS N-chlorosuccinimide NMR nuclear magnetic resonance NMO N-methylmorpholine N-oxide nOe nuclear Overhauser effect o ortho OMB ortho -methoxybenzyl p para pet. ether petroleum ether 40-60 °C Ph phenyl PMB para-methoxybenzyl PMP para-methoxyphenyl ppm parts per million PPTS pyridinium para -toluenesulfonate Pr propyl Py pyridine q quartet R alkyl group RAMP (R)-(+)-1-amino-2-methoxymethylpyrrolidine Rf retardation factor 8 rt room temperature s singlet SAMP (S)-(-)-1-amino-2-methoxymethylpyrrolidine sat. saturated s-BuLi secondary-butyllithium SEM (trimethylsilyl)ethoxymethyl SET single electron transfer sept septet sext sextet sol. solution t triplet t tertiary TBAF tetra-n-butylammonium fluoride t-BuLi tertiary-butyllithium Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMEDA tetramethylethylenediamine TMG tetramethyl guanidine TMS tetramethylsilane Tol toluene Ts p-toluenesulfonyl TTFA thallium trifluoroacetate 9 Contents Abstract 3 Acknowledgements 5 Abbreviations 6 Part 1: Stereoselective Synthesis of Pyrrolidinones via Nitro-Mannich Reaction 1.0 Introduction 14 1.1 The Nitro-Mannich Reaction 14 1.2 Metal-Catalysed Nitro-Mannich Reactions 17 1.3 The Organocatalytic Nitro-Mannich Reaction 24 1.4 Cascades Involving the Nitro-Mannich Reaction 29 1.5 The Nitro-Mannich Reaction in Synthesis 33 1.6 Stereoselective Conjugate Addition to Nitroalkenes 36 1.6.1 Substrate/Auxillary Controlled Conjugate Addition 37 1.6.2 Catalytic Conjugate Addition 39 1.6.3 Conjugate Addition to Nitroacrylates 41 1.7 Stereoselective Synthesis of Pyrrolidinones 46 1.8 Tandem Processes for the Synthesis of Pyrrolidinones 52 2.0 Proposed Research 55 3.0 Results and Discussion 56 3.1 Initial Result 56 3.2 Optimisation 57 3.3 Reaction Scope 62 3.4 Confirmation of Relative Stereochemistry 68 3.5 Further Functionalisation 69 3.6 Origins of Diastereoselectivity 73 3.7 Asymmetric Methodology 80 3.8 Further Development 82 4.0 Conclusions and Future Studies 85 4.1 Conclusions 85 4.2 Future Studies 87 5.0 Experimental 90 10 5.1 General Experimental Details 90 5.2 Analytical Instruments and Characterisation 90 5.3 Purification of Solvents and Reagents 91 5.4 Experimental Procedures 92 5.4.1 Preparation of Imines and Nitroalkenes 92 5.4.2 Synthesis of Pyrrolidinones 98 5.4.3 Further Functionalisation 117 6.0 Appendices 127 7.0 References for Part 1 133 ------------------------------------------------------ Part 2: Towards the Synthesis of Popolohuanone E 1.0 Introduction 140 1.1 Popolohuanone
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