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Synthesis of Biologically Active Indole-Fused Heterocyclic Derivatives

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Synthesis of Biologically Active Indole-Fused Heterocyclic Derivatives View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Research Online University of Wollongong Research Online University of Wollongong Thesis Collection 1954-2016 University of Wollongong Thesis Collections 2005 Synthesis of biologically active indole-fused heterocyclic derivatives Waya Sengpracha University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation Sengpracha, Waya, Synthesis of biologically active indole-fused heterocyclic derivatives, PhD thesis, Department of Chemistry, University of Wollongong, 2005. http://ro.uow.edu.au/279 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] i SYNTHESIS OF BIOLOGICALLY ACTIVE INDOLE- FUSED HETEROCYCLIC DERIVATIVES A thesis submitted in fulfillment of the requirements of the award of the degree DOCTOR OF PHILOSOPHY from UNIVERSITY OF WOLLONGONG by Waya Sengpracha, M.Sc. (Hons.) Department of Chemistry Wollongong, Australia February 2005 ii CERTIFICATION I, Waya Sengpracha, declare that this thesis, submitted in fulfillment of the requirements for the award of Doctor of Philosophy, in the Department of Chemistry, University of Wollongong, is wholly my own work unless otherwise referenced or acknowledged. The document has not been submitted for qualifications at any other academic institution. Waya Sengpracha 10 February 2005 iii PUBLICATIONS 1. A free radical cyclisation approach to indolo-benzodiazocine derivatives (Bremner, J.; Sengpracha, W. Tetrahedron, 2005, 61, 941-953) 2. An iodoacetamide-based free radical cyclisation approach to the 7,12-dihydro- indolo[3,2-d][1]benzazepin-6(5H)-one (Paullone) system (Tetrahedron, submitted) iv TABLE OF CONTENTS CERTIFICATION ii PUBLICATIONS iii TABLE OF CONTENTS iv LIST OF FIGURES x LIST OF SCHEMES xi LIST OF TABLES xv LIST OF ABBREVIATIONS xvii ABSTRACT xx ACKNOWLEDGEMENTS xxi Chapter 1 Introduction 1 1.1 Introduction to indoles................................................................................................... 1 1.1.1 Bioactive indoles 2 1.1.1.1 Mono indoles 2 1.1.1.2 Bis-indoles 3 1.1.1.3 Annelated indoles 5 1.2 Indole synthesis .............................................................................................................. 7 v 1.3 Indole fused seven- or eight-membered ring systems ................................................. 9 1.3.1 Synthesis of indole-1,2-fused seven or eight membered ring systems 9 1.3.1.1 Bond formation to C-2; ring closure via N-substituted indoles 10 1.3.1.2 Bond formation to N-1; ring closure via 2-substituted indoles 12 1.3.1.3 Medium ring formation via 1,2-disubstituted indoles 14 1.3.1.4 Indole ring formation 19 1.3.2 Synthesis of indole-2,3-fused seven or eight membered ring systems 19 1.3.2.1 Ring closure at C-3 via 2-substituted indoles 20 1.3.2.2. Ring closure via 3-substituted indoles 22 1.3.2.3 Ring closure via 2,3-disubstituted indoles 23 1.3.2.4 Ring expansion routes to fused indoles 26 1.3.2.5 Indole ring formation 28 1.4 Aims of the project....................................................................................................... 29 1.5 Thesis outline ................................................................................................................ 30 Chapter 2 Indole-fused eight membered ring heterocycles 32 2.1 Introduction.................................................................................................................. 32 2.2 Free radical cyclisation................................................................................................ 33 2.2.1 Proposed synthetic approach to indole fused eight-membered rings 38 2.2.2 Preparation of amine starting materials (145) 38 vi 2.2.3 N-methylation of primary amines 39 2.2.4 N-benzylation of primary amines 42 2.2.5 Reductive amination 43 2.2.6 N-acylation of primary amine 46 2.2.7 Preparation of chloroacetamides 49 2.2.8 Preparation of iodoacetamides 56 2.2.9 Preparation of bromoacetamides 59 2.2.10 Synthesis of benzodiazocinone derivatives using free radical cyclisation 61 2.2.11 Debenzylation of N-benzyl substituted indolo[2,1-d][1,5]- benzodiazocine-6-ones 69 2.3 Attempted metal-mediated cyclisation....................................................................... 70 2.3.1 Silver-mediated cyclisations 70 2.3.2 Palladium-mediated cyclisation 71 2.3.3 Indium-mediated cyclisation 73 2.3.4 Zinc-silver couple mediated cyclisation 74 2.4 Summary and Conclusions.......................................................................................... 76 Chapter 3 Indole seven membered ring heterocycles 78 3.1 Introduction.................................................................................................................. 78 3.2 Proposed synthetic approach to indole fused seven membered rings ..................... 82 vii 3.3 Preparation of 2-(2΄-aminophenyl)indoles 212.......................................................... 83 3.3.1 Acylation of 1H-indoles with isocyanates 85 3.3.2 N-alkylation reactions of ureas 88 3.3.3 Palladium cyclisation of ureas 89 3.4 Preparation of chloroacetamides................................................................................ 92 3.4.1 Hydrolytic ring opening of the cyclised products 93 3.4.2 Chloroacetylation 94 3.4.3 Preparation of iodoacetamides 97 3.5 Radical cyclisations ...................................................................................................... 99 3.6 Debenzylation ............................................................................................................. 105 3.7 Summary and Conclusions........................................................................................ 106 Chapter 4 Synthetic approach to the marine natural product iheyamine A 107 4.1 Introduction................................................................................................................ 107 4.2 Proposed synthetic routes.......................................................................................... 109 4.3 Synthesis of N-substituted isatins ............................................................................. 111 4.4 Synthesis of spiro compounds ................................................................................... 113 4.5 Attempted acid mediated rearrangement................................................................ 118 viii 4.6 Rearrangement of spirocyclic oxindoles 120 4.6.1 Preparation and rearrangement of carbinolamines 123 4.6.2 Rearrangement 127 4.7 Attempted N-demethylation 131 4.8 Summary and Conclusions 132 Chapter 5 Antimicrobial Assay 133 5.1 Introduction 133 5.2 Resistance to antibacterial agents 133 5.3 Resistance to antimalarial agents 135 5.4 Antimicrobial assays 136 5.5 Results of the antibacterial testing 138 5.6 Results of antimalarial testing 142 Chapter 6 Conclusions and Future Directions 144 6.1 Conclusions 144 6.2 Future Directions 146 ix Chapter 7 Experimental 147 7.1 General procedure 147 7.2 Experimental for Chapter 2 148 7.3 Experimental for Chapter 3 207 7.4 Experimental for Chapter 4 241 References 250 Appendix 260 x LIST OF FIGURES Figure 2-1. Mechanism of direct N-alkylation. 42 Figure 3-1. General chemical structure and CDK1/cyclin B inhibition values for several paullones 78 Figure 4-1. A colonial ascidian, Polycitorella sp. (purple) 108 Figure 4-2. 1H NMR spectrum of the carbinolamine 269b. 127 Figure 4-3. 1H NMR spectrum of bis-indole fused seven membered rings 270. 129 Figure 5-1. Staphylococcus aureus bacteria (Golden Staph). 134 Figure 5-2. The generic indolo-benzodiazocine structure. 137 xi LIST OF SCHEMES Scheme 1-1. Lithiation of N-substituted indoles. 8 Scheme 1-2. Example of Diels- Alder reaction of 2-vinylindole. 9 Scheme 1-3. Photochemical cyclisation of chloroacetamides. 10 Scheme 1-4. Intramolecular nitrile oxide-olefin cycloaddition. 11 Scheme 1-5. Radical cyclisation of alkylhalides. 11 Scheme 1-6. Cyclodehydration via a Bischler Napieralski type reaction. 12 Scheme 1-7. Cyclisation via intramolecular Pauson-Khand reactions. 16 Scheme 1-8. Preparation of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indoles. 17 Scheme 1-9. Preparation of indolo[2,1-c][1,4]benzodiazepine derivatives. 18 Scheme 2-1. Photolysis
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