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Synthesis of Azetidines, Γ-Lactams, Fused Furan Bispyrrolidines and 2-Pyrazolines: Towards Medical Application

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Synthesis of Azetidines, Γ-Lactams, Fused Furan Bispyrrolidines and 2-Pyrazolines: Towards Medical Application School of Chemistry Synthesis of azetidines, γ-lactams, fused furan bispyrrolidines and 2-pyrazolines: Towards medical application By Mariwan A. Hama Salih A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Project supervisor: John S. Fossey Co-Supervisor: Ferenc Mueller September 2015 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Contents Abstract ......................................................................................................................................................... ix Aim of the project .......................................................................................................................................... x Chapter One .................................................................................................................................................. xi 1. Introduction ................................................................................................................................................ 1 1.1 Azetidine .................................................................................................................................................. 1 1.1.1 Synthesis of azetidine derivatives ................................................................................................. 2 1.1.2 Baldwin rule of ring closure ........................................................................................................15 1.1.3 Reactions of azetidines ................................................................................................................21 1.1.4 Application of azetidines .............................................................................................................24 1.2 Pyrrolidin-2-one (γ-lactam) ....................................................................................................................32 1.3 Fused tricyclic ring system .....................................................................................................................35 1.4 Pyrazoline ...............................................................................................................................................37 Chapter Two .................................................................................................................................................42 2. Results and discussion ..............................................................................................................................43 2.1 Racemic azetidine synthesis ...................................................................................................................43 2.1.1 Synthesis of intermediates ...................................................................................................................44 2.1.2 Cyclisation of racemic homoallylamines ............................................................................................50 2.2 Enantiopure azetidine synthesis .............................................................................................................54 2.2.1 Synthesis of enantiopure homoallylamines .........................................................................................54 2.2.2 Cyclisation of enantiopure homoallylamines ......................................................................................56 Chapter Two .................................................................................................................................................60 2.3 γ-Lactams synthesis................................................................................................................................61 2.3.1 Synthesis of 3-methyl substituted homoallylamines intermediates .....................................................61 2.3.2 Cyclisation of 3-methyl substituted homoallylamines ........................................................................66 2.3.3 Cyclisation of enantio enriched 3-methyl substituted homoallylamines .............................................83 2.4 Furan bis-pyrrolidine synthesis ..............................................................................................................86 2.4.1 Synthesis of 3-phenyl substituted homoallylamines intermediates .....................................................86 2.4.2 Cyclisation of 3–phenyl substituted homoallylamines ........................................................................88 ii Chapter Two .................................................................................................................................................95 2.5 Synthesis of 3-gem-dimethyl substituted azetidine ................................................................................96 2.5.1 Attempt toward synthesis of 4-gem-dimethyl substituted homoallylamine ........................................96 2.5.2 Cyclisation of 2-gem-dimethyl substituted homoallylamines .............................................................97 2.6 Towards the synthesis of 3-substituted azetidines .................................................................................99 2.6.1 Synthesis of 2-methyl substituted homoallylamine intermediate ........................................................99 2.6.2 Cyclisation attempt of 2-methyl substituted homoallylamines .........................................................100 2.7 Cyclisation attempt of cyclic homoallylamine .....................................................................................101 Chapter Two ...............................................................................................................................................105 2.8 Pyrazoline synthesis .............................................................................................................................106 2.8.1 Synthesis of homoallylhydrazine intermediates ................................................................................106 2.8.2 Cyclisation of homoallylhydrazine ...................................................................................................110 Chapter Three .............................................................................................................................................117 3. Biological applications of azetidines and γ-lactams ...............................................................................118 3.1 Biological activity ................................................................................................................................118 3.2 Zebrafish ..............................................................................................................................................118 3.3 Previous work in biological activity .....................................................................................................119 3.4 γ-Lactam screening ..............................................................................................................................121 3.5 Anti-inflammatory activity ...................................................................................................................133 3.6 Anti-bacterial activity ...........................................................................................................................134 Chapter Four ...............................................................................................................................................136 4. Conclusion ..............................................................................................................................................137 Chapter Five ...............................................................................................................................................139 5. Future work ............................................................................................................................................140 Chapter Six .................................................................................................................................................142 6. Experimental Part ...................................................................................................................................143 General Procedures ....................................................................................................................................143 Characterisation data ..................................................................................................................................150 Characterisation data for the synthesised enantiopure azetidine compounds: ...........................................173 Characterisation data for the synthesised pyrrolidin-2-one compounds: ...................................................179 iii Characterisation data for the synthesised intermediates and fused tricyclic compounds: ..........................204 Characterisation
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