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THE UNIVERSITY of HULL Analogues of Bredinin: Synthesis of 5-Hydroxyimidazoles from Acyclic Precursors Being a Thesis Submitte

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THE UNIVERSITY of HULL Analogues of Bredinin: Synthesis of 5-Hydroxyimidazoles from Acyclic Precursors Being a Thesis Submitte THE UNIVERSITY OF HULL Analogues of Bredinin: Synthesis of 5-Hydroxyimidazoles from Acyclic Precursors being a Thesis submitted for the Degree of Doctor of Philosophy in the University of Hull by Danielle Fiona Middleton B.Sc. (Hons) Chemistry with Molecular Medicine September 2008 Abstract Compared to 1-substituted-5-aminoimidazoles relatively few 1-substituted-5- hydroxyimidazoles have been reported; however, an interesting 1-substituted-5- hydroxyimidazole is the immunosuppressive agent bredinin, which shows antiviral 1, antimalarial 2, antitumour 3,4 and antiarthritic 5 activities. Bredinin is obtained naturally by extraction from a fermentation process, and current synthetic strategies for the synthesis are ambiguous and don’t easily allow for the synthesis of analogues. Surprisingly, relatively few analogues of bredinin are known hence a convenient route to such types of compounds would be useful in providing a library of compounds for structural activity studies to be made. The aim of the present study was to develop a synthetic strategy which employed inexpensive and readily available acyclic precursors to synthesise a library of analogues of bredinin. An advantage of using acyclic precursors to synthesise imidazoles is that the introduction of substituents, in particular, those in the 1-position is unambiguous. Therefore, our approach has been to explore an efficient and general route to 1- substitued-5-hydroxyimidazoles employing inexpensive and readily available starting materials. Our initial target was to synthesise ethyl 1-substituted-5-hydroxyimidazole-4- carboxylates since such ester intermediates have the potential to be converted to a wide variety of related 4-substituted imidazoles. A variety of ethyl 1-substituted-5- hydroxyimidazole-4-carboxylates were synthesised. Those synthesised using lipophilic amines at position 1 of the imidazole ring (structures 39-43), were obtained in high yields and easily purified. However, those synthesised using polar amines at position 1 (structures 43-45), were more difficult to isolate and purify due to their increased hydrophilic nature. In addition, the adopted strategy offers the opportunity to introduce a variety of substituents in the 2-position of the imidazole ring (structures 48-49), however this increase in chain length at position 2 had a direct effect on the yield of the imidazole obtained. The longer the chain length, the lower the yields, due to the steric hindrance experienced in the cyclisation step of the synthetic sequence. i In summary a novel convergent synthetic strategy was devised and both ethyl 1,2- substituted-5-hydroxyimidazole-4-carboxylates, with both aryl and alkyl groups at position 1, and benzyl 1-benzyl-5-hydroxyimidazole-4-carboxylate were successfully synthesised. Both lipophilicity and steric bulk were found to play a crucial role in the successful cyclisation and subsequent isolation and purification of the imidazoles, and a compromise between the two must be achieved to give the optimal reaction conditions. In an attempt to gain a greater understanding of these ethyl 1-substituted-5- hydroxyimidazole-4-carboxylates systems, their reactivity under different reactions conditions was assessed. Ethyl 1-benzyl-5-hydroxyimidazole-4-carboxylate was used as the model system and was found to be stable to all targeted manipulation at position 2 and 4 of the imidazole ring. Additionally, all attempts to protect the 5-hydroxyl function, to allow the subsequent manipulation of the ethyl ester, were also unsuccessful. The unexpected benzylation of the nitrogen at position 3 of the imidazole ring, to form the quaternary ammonium salt, confirms that this is the most nucleophilic atom within the imidazole ring system. A novel linear synthetic strategy using acyclic precursors was developed which enabled the addition of substituents in positions 1, 2, 4 and 5 of the imidazole ring unambiguously. A particular advantage of this route is that it would be possible to synthesise 4-substituted-5-hydroxyimidazoles. An interesting difference between the two synthetic routes is that nucleosides of the 5- hydroxyimidazoles were successfully synthesised using the linear synthetic strategy, however they could not be synthesised using the convergent strategy. This indicates the important role nucleophilicity could play in the intramolecular cyclisation step of the convergent synthetic strategy. The most important implications of the present study are the development of two separate, unambiguous synthetic routes to the 5-hydroxyimidazoles, employing inexpensive acyclic precursors. The routes could provide access to a variety of substituted 5-hydroxyimidazoles in order to build a library of these compounds. ii Acknowledgements I recognize that this research would not have been possible without the financial assistance of EPSRC, the University of Hull and the Department of Chemistry. I would like to express my gratitude to my supervisors, Dr. Andrew Boa and Dr. Grahame Mackenzie, and all of the technical staff within the department who have helped me along the way. Thank you to all of the guys from C222, both past and present - Diepreye, Lisa, Matt, Elliot, Sylvain, and Alberto - you all made my experience so much more fun and meaningful. To Matt and Elliot particularly, for all of the thoughts you’ve contributed to my written work, this thesis wouldn’t have been the same if it wasn’t for all of your contributions and for that I can’t thank you enough. To all of my friends in both Hull and Cambridge, who have particularly helped me over the last three years, with special thanks to Becky Batchelor, Becky Kift, Jon, Leanne, Chris, Rebekah, Steve, Jenny, Sheryl, Jagdip, Lozzie, Kelly, Clare, Emma and Andrew Wright, Becky Button, Beth, and Becci Webb. To all of you, I extend my deepest appreciation. To Rob, Neecey and James Rowbotham – I will always be greatful to you for all of the loving support you have given me over the last three years, and for providing me with a sanctuary where I could get away when it all just got too much. Thank you. To the Middleton’s - Dad, Mum, Damian and Christopher - my fantastic family. Thank you for believing in me, for always encouraging me to go beyond my past achievements and continue to develop my talents and potential. Thank you for teaching me to be a big dreamer and always showing me that I can live beyond expectations and in such a way that the impossible is just an everyday occurrence. I couldn’t ask for a better family than I have in you, and it is to you who I dedicate this work - I couldn’t have achieved this without your support. I love you. Thank you. iii To Scotty - my rock - without whose love, support, understanding, encouragement and editing assistance, I would not have finished this thesis. You make the journey so much more enjoyable by putting a smile on my face every day. I hit the jackpot when I met you! I love you. Thank you. Finally, I would like to thank everybody who was important to the successful realisation of this thesis, as well as expressing my apologies that I could not mention you all personally one by one. To everyone who has helped me along the way, I am eternally grateful - thank you! iv ABSTRACT i ACKOWLEDGEMETS iii COTETS v OMECLATURE viii CHAPTER OE - MALARIA 1 1.1 Introduction 2 1.2 Plasmodium falciparum 4 1.3 Current Therapeutic Approaches to the Treatment of P. falciparum Infections 6 1.3.1 Blood Schizonticides 7 1.3.2 Tissue Schizonticides 11 1.3.3 Both Blood and Tissue Schizonticides 12 1.3.4 Nucleic Acid Inhibitors/Antimetabolites 13 1.4 Future Outlook 16 CHAPTER TWO - THE BIOSYTHESIS OF PURIE AD PYRIMIDIES 17 2.1 Introduction 18 2.2 Nucleosides, Nucleotides and Nucleic Acids 19 2.3 Purines 22 2.3.1 De novo Purine Biosynthetic Pathway 22 2.3.2 Inosine Monophosphate Dehydrogenase 26 2.4 Pyrimidines 29 2.4.1 De novo Pyrimidine Biosynthetic Pathway 29 2.4.2 Orotidine 5’-Monophosphate Decarboxylase 31 2.5 Summary 37 CHAPTER THREE - THE CHEMICAL SYTHESIS AD PROPERTIES OF A SELECTIO OF 5-HYDROXYIMIDAZOLES 38 3.1 Introduction 39 3.2 Bredinin 40 3.3 Interesting Biological Properties of Bredinin 43 3.3.1 Immunosuppressive 43 3.3.2 Antitumour 44 3.3.3 Antiviral and Antimicrobial 46 3.3.4 Antiarthritic 46 3.3.5 Antimalarial 47 3.4 Comparison of some Bredinin Analogues Currently Known 48 3.4.1 AICAR 48 3.4.2 Ribavirin 49 3.4.3 Levovirin 50 3.4.4 Viramidine 50 3.4.5 EICAR 51 3.4.6 Pyrazofurin 51 v 3.5 Methods of Synthesis of 5-Hydroxyimidazole-4-Carboxylates 53 3.5.1 Natural Product Synthesis 53 3.5.2 Direct Glycosylation of Preformed Imidazoles 53 3.5.3 Degradation/Ring Opening of Purine Nucleosides or Nucleotides 54 3.5.4 Diazotization of Purine Nucleosides or Nucleotides 60 3.5.5 Cyclisation of Acyclic Precursors 61 3.6 Summary 65 CHAPTER FOUR - THE CHEMICAL SYTHESIS OF ETHYL 5- HYDROXYIMIDAZOLE-4-CARBOXYLATES 66 4.1 Introduction 67 4.2 Rationale 68 4.3 Retrosynthetic Analysis 70 4.4 Convergent Synthetic Route 71 4.4.1 Synthetic Strategy 73 4.4.2 Development of Synthetic Strategy 75 4.4.3 Ethyl 1-Subtituted 5-Hydroxyimidazole-4-carboxylates 81 4.4.4 2-Subtituted Ethyl 1-Benzyl-5-hydroxyimidazole- 4-carboxylates 90 4.4.5 Benzyl 1-Benzyl-5-hydroxyimidazole-4-carboxylate 92 4.5 Linear Synthetic Route 95 4.5.1 Synthetic Strategy 97 4.5.2 Development of Synthetic Strategy 99 4.6 Summary 102 CHAPTER FIVE - THE REACTIVITY OF ETHYL 5- HYDROXYIMIDAZOLE- 4-CARBOXYLATES 103 5.1 Introduction 104 5.2 Reactivity Study of Ethyl 1-Benzyl-5-hydroxyimidazole- 4-carboxylate 105 5.2.1 Reactivity at C-2 105 5.2.2 Reactivity
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