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A Novel Synthetic Route Towards Anti-Inflammatory Mediator: Resolvin E1

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A Novel Synthetic Route Towards Anti-Inflammatory Mediator: Resolvin E1 A thesis submitted in partial fulfilment of the degree of Doctor of Philosophy A Novel Synthetic Route Towards Anti-Inflammatory Mediator: Resolvin E1 Danielle L. Pearson Supervisors: Dr Marc C. Kimber, Dr Gareth J. Pritchard, and Dr Martin R. Lindley © Danielle Pearson 2018 Thesis Abstract The health benefits of fish oil supplementations have been proven to be effective by several studies which are discussed in this thesis. It was found that these compounds had potent anti-inflammatory properties and since then has prompted much research into the use of these compounds as potential treatments for chronic inflammation based diseases, where the overuse of current anti-inflammatory drugs cause many problems with undesired side-effects. The aim of this research is to study the bioactivity of resolvin E1 and various analogues, and to determine a novel route towards resolvin E1 natural product so that bioactivity tests may be conducted in comparison of synthetically produced resolvin E1 and naturally extracted resolvin E1. The initial aim of this research was to develop a range of analogues of a fragment of Resolvin E1. This was so that a series of compounds could be produced with various R groups to identify any structure-activity relationships for this part of the natural product. There is one stereocentre in this fragment of resolvin E1 and it was decided that a racemic version of these compounds would be tested for bioactivity, and if any of the compounds had significant anti-inflammatory properties then the R and S versions could be separated, allowing for the testing of both enantiomers to determine which gave the most potent anti-inflammatory response. This led to the creation of several novel fragments and their biological testing. The secondary aim of the project was to complete the total synthesis of the resolvin E1 natural product. We devised a novel route towards resolvin E1 which used MIDA boronate protecting group to introduce a fixed trans double bond which was useful in a compound with multiple alkene systems. Resolvin E1 also contains three stereocentres, the synthesis from the fragment work was recycled to begin the synthesis, and made use of 1,2:5,6-di-O-isopropylidene-D-mannitol and Noyori’s catalyst to setup the stereocentres. The use of new MIDA-boronate moieties were also explored in order to develop a new, efficient synthesis toward resolvin E1. i Acknowledgments Firstly, I would like to thank my supervisors, Dr Marc Kimber, Dr Gareth Pritchard and Dr Martin Lindley, for giving me the opportunity to do this project. Thank you, Marc and Gaz for all of your help and support in and out of lab, you’ve kept me motivated throughout the project and always full of ideas to help me through any chemistry/career/life problems I might have. Thank you for keeping your patience with me during group meetings and for the trips to the pub, you have both gone above and beyond the call of duty to help me and I could not have asked for a better pair of supervisors. I would also like to thank Luke Baker for all the biology lessons and for testing my precious compounds. Al Daley, thanks for your help with everything in the lab and for showing me how to use many of the analytical instruments. Thank you to Mark Edgar for all your help NMR-wise. My time in lab would not have been the same without all the people who have worked there. Thanks to Nat, Yamin, Kay, Yassir and everyone else in lab who managed to keep their cool and not destroy my phone whilst my playlist (mainly consisting of Bastille and Imagine Dragons ) was blaring out every day… I like to think some of you, maybe, enjoyed the music towards the end?! Big thank you to Rob, my PhD would not have been the same without you, thank you for the help, laughs, hugs and the many coffee/pepsi max trips. Maybe we could persuade EHB to serve us some chilli, chips and cheese one last time?! To all my wonderful friends in Loughborough, Nottingham and everywhere else, thank you for your support. Special mentions to my Faraday family, Vicky, and Stewart (Bej!). For team Azkabants, Robyn, and Jake, you are awesome -let’s hope operation PhD is as successful as Orange Woo Woo. Thanks to Josh and Isobel who always try (and fail) to improve my fashion sense, and for teaching me that it is fun to be a chimp. To Mark, thank you for everything. Your support throughout my PhD has meant so much to me. I know that stress has not always brought out my better side, especially after several long days/weeks/months in the lab of things not working, so thank you for being patient and never complaining about the major ups and downs. Thank you for trying to fix my oven in JP, buying my favourite playstation games for me, for everything since then and for basically, being the pasta king. ii Thank you to Mum and Dad, I would not be writing this thesis without your support, emotional and financial. You always manage to bring me back down to Earth when everything seems too stressful. Thank you for listening to me chatter/complain about chemistry and for attending all my music concerts, having you there has meant more than I can say. Finally, I would like to thank the wonderful people at Pepsi Co, Classic FM and the creators of Gilmore Girls. The caffeinated drinks, smooth musics and fast-paced comedic drama, have been reliable pick-me-ups throughout the past three years. iii List of Abbreviations AA Arachidonic acid BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) COSY Correlated Spectroscopy COX Cyclooxygenase CSA Camphorsulfonic acid CTABr Cetyltrimethylammonium bromide DIBAL-H Diisobutyl aluminium hydride DEPT Distortionless enhancement by polarization transfer DHA Docosahexaenoic acid (DHQD)2PHAL Hydroquinidine 1,4 – phthalazinediyl diethyl DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO Dimethyl sulfoxide DPEN Diphenylethylenediamine E.Coli Escerichia coli Ee Enantiomeric excess Equiv. Equivalents EPA Eicosapentaenoic acid ESI Electrospray ionisation FMOC 9-fluoroenyl-methoxy carbonyl GPRC G-protein coupled receptors iv h Hour HEPE Hydroxy-eicosapentaenoic acid HPLC High performance liquid chromatography HRMS High resolution spectrometry IL Interleukin IR Infrared LC Liquid chromatography LOX Lipoxygenase LTs Leukotrienes mCPBA Meta-chloroperoxybenzoic acid MIDA N-Methyliminodiacetic acid Mins Minutes MS Mass Spectrometry NMR Nuclear magnetic resonance NSAIDS Non- steroidal anti-inflammatory drugs PGs Prostaglandins Ph Phenyl PMNs Polymorphonuclear cells PPh3 Triphenyl phosphine ppm Parts per million PUFAs Polyunsaturated fatty acids r.t Room temperature RvD1 Resolvin D1 v RvD2 Resolvin D2 RvD5 Resolvin D5 RvD6 Resolvin D6 RvE1 Resolvin E1 RvE2 Resolvin E2 RvE3 Resolvin E3 SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl THF Tetrahydrofuran TLC Thin layer chromatography TBS Tert-butyl dimethyl silyl TBDPS Tert-butyl diphenyl silyl TMS Trimethyl silyl Tf Triflate Ts Tosylate Ts-Cl 4-Toluenesulfonyl chloride UV Ultraviolet vi Table of Contents Thesis Abstract .................................................................................................................. i Acknowledgments ............................................................................................................ ii List of Abbreviations ....................................................................................................... iv 1. Introduction ................................................................................................................... 1 1.1 Inflammation ........................................................................................................... 3 1.2 Resolvins ................................................................................................................. 5 2. Previous Syntheses of Resolvins and Related Compounds ........................................ 10 2.1 E Resolvins............................................................................................................ 10 2.2 D Resolvins ........................................................................................................... 24 3. MIDA-Boronates ........................................................................................................ 34 4.0 Conclusions ............................................................................................................... 42 5. Project Aims ............................................................................................................... 44 6. Results and Discussion ............................................................................................... 49 6.1 Resolvin E1 Fragment Synthesis .......................................................................... 49 6.2 Biological Testing ................................................................................................. 68 6.3 MIDA Boronate Epoxide ring opening ................................................................. 72 6.4 Resolvin E1 Natural Product Substrate Synthesis ................................................ 86 6.5 Resolvin E1 Natural Product Synthesis ................................................................ 93 7. Conclusions and Future Work .................................................................................. 117 8. Experimental ............................................................................................................. 119 8.1 General ...............................................................................................................
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