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Synthetic Studies Towards Analogs of Protectin D1

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Synthetic Studies Towards Analogs of Protectin D1 Synthetic Studies Towards Analogs Of Protectin D1 Thesis for the degree Master of Pharmacy Mai El-khatib School of Pharmacy Faculty of Mathematics and Natural Sciences UNIVERSITY OF OSLO 2016 Synthetic Studies Towards Analogs Of Protectin D1 Thesis for the degree Master of Pharmacy Mai El-khatib School of Pharmacy Faculty of Mathematics and Natural Sciences UNIVERSITY OF OSLO 2016 © Mai El-khatib, 2016 SYNTHETIC STUDIES TOWARDS ANALOGS OF PROTECTIN D1 Mai El-khatib http://www.duo.uio.no Printed in Norway: Reprosentralen, Universitetet i Oslo II ”The secret of life, though, is to fall seven times and to get up eight times.” - Paulo Coelho III IV Acknowledgements The work presented in this master’s thesis has been undertaken between June 2015 and June 2016 at the school of pharmacy, department of pharmaceutical chemistry, University of Oslo. First of all, I would like to thank my supervisor Professor Trond Vidar Hansen for his continuous support and motivation throughout the whole year. I am grateful for the inspiring conversations and the suggestions we both exchanged. Your brilliance and love for chemistry has been a great source of motivation. My sincere gratitude also goes to Associate Professor Anders Vik who has also been motivating me and providing me with insightful comments and encouragement. Without his support I would not be able to conduct this research. I also wish to acknowledge both Dr. Jørn Tungen and Dr. Marius Aursnes who have managed to make me the lab-nerd I am today and also for sharing their expertise. It was a pleasure working and laughing with you. You always made my day. Thank you. I would also like to express my dearest gratitude to Mats Wilhelmsen for the continuous support and for the motivation throughout this thesis. Last but not least, I want to thank my friends and family, especially my parents, Mai and Hisham El-khatib for their love, caring, continuous spiritually support and the encouragement they have given me through my whole life. This thesis is dedicated to my mom. Our dream is now fulfilled. Mai El-khatib Oslo, May 2016 V Abstract Resolution of the inflammatory process by oxygenated derivatives of eicosapentaenoic acid, docosahexaenoic acid and n-3 docosapentaenoic acid, is an important field of study. It has led to the discovery of certain derivates of the fatty acids, namely specialized pro-resolving mediators. Their ability to induce the resolution of an active inflammatory process and thus prevent several connected diseases is increasingly becoming acknowledged. Protectin D1 is a potent anti-inflammatory and pro-resolving derivative from docosahexaenoic acid. However, protectin D1 is metabolized rapidly in vivo once biosynthesized. The synthesis of new analogs may result in novel, related compounds. These may in turn prove to be beneficial having structural features, which render them less prone to rapid metabolism, and thus extending the wanted biological activities of the parent, specialized pro-resolving mediator. The synthesis of two hitherto unknown fatty acid analogs discussed in this thesis is based on the initial synthesis of the three main fragments of each compound. Both analogs are then to be assembled by combining an alpha-, omega- and middle fragment - the two latter building blocks being identical in all cases. In this thesis, these four needed fragments have been successfully synthesized and are ready for further assembly. Future work includes assembly of said fragments into the two wanted protectin D1-analogs and screening for any potential biological effects. VI Graphical Abstract The omega-fragment O OTES OH The middle fragment TBSO O S TBSO Br N S Br O Alpha fragments CO2H IPh3P CO2Me O HO O OH BrPh3P O O HO O OH IPh3P O VII Potential assembly of the fragments 1) TBSO Br O OTBS + Br CO2Me IPh3P CO2Me 2) OTBS OTES Br CO2Me + OH OH CO2H 1) TBSO Br O OTBS O + O Br O O O IPh3P O 2) OTBS O OTES O Br O + OH OH O CO H 2 VIII Abbreviations AA Arachidonic acid ALA Alpha-linolenic acid BLT1 Leukotriene B4 Receptor ChemR23 Chemokine like receptor 1 COX Cyclooxygenase enzyme COX-1 Cyclooxygenase-1 COX-2 Cyclooxygenase-2 CSA Camphorsulfonic acid DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DHA Docosahexaenoic acid DIBAL-H Diisobutylaluminum hydride DMAP 4-Dimethylaminopyridine DMP Dess-Martin periodinane DMSO Dimethyl sulfoxide EPA Eicosapentaenenoic acid GPCR G protein-coupled receptor HDHA Hydroxydocosahexaenoic acid HETE Hydroxyeicosatetraenoic acid HMPA Hexamethylphosphoramide HpDHA Hydroperoxydocosahexaenoic acid HpDPA Hydroxyperoxydocosapentaenoic acid HpETE Hydroperoxyeicosatetraenoic acid HRMS High-resolution mass spectrometry LDA Lithium diisopropylamide LOX Lipooxygenase enzyme IX LTB4 Leukotriene B4 LXA4 Lipoxin A4 LXB4 Lipoxin B4 MaR Maresin MRM Multiple reaction monitoring n-3 DPA n-3 docosapentaenoic acid NaHMDS Sodium bis(trimethylsilyl)amide NSAID Nonsteroidal anti-inflammatory drug PCC Pyridinium chlorochromate PD1 Protectin D1 PGE2 Prostaglandin E2 PMN Polymorph nuclear neutrophil PUFA Polyunsaturated fatty acid RedAl® Sodium bis(2-methoxyethoxy)aluminum hydride RvD Resolvin of the D-series RvE Resolvin of the E-series Sn(OTf)2 Tin(II) trifluoromethanesulfonate SPM Specialized pro-resolving lipid mediator TBAF Tetrabutylammonium fluoride TBDPSCl tert-Butyl(chloro)diphenylsilane TBS tert-Butyldimethylsilyl TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate TES Triethylsilyl VLDL Very Low Density Lipoprotein X Table of Contents Acknowledgements………………………………………………………………………..….V Abstract………………………………………………………………………………………VI Graphical abstract…………………………………………………………………………...VII Abbreviations………………………………………………………………………………...IX 1 Introduction .......................................................................................................................... 1 1.1 ω-3 Polyunsaturated fatty acids and health benefits ..................................................... 1 1.2 Inflammation ................................................................................................................. 2 1.2.1 Acute inflammation ................................................................................................ 2 1.2.2 Chronic inflammation ............................................................................................ 3 1.3 Enzymes involved ......................................................................................................... 4 1.3.1 Lipoxygenases ........................................................................................................ 4 1.3.2 Cyclooxygenases .................................................................................................... 5 1.4 Specialized pro-resolving mediators ............................................................................. 5 1.4.1 Lipoxins .................................................................................................................. 7 1.4.2 E-series Resolvins .................................................................................................. 8 1.4.3 D-series Resolvins .................................................................................................. 9 1.4.4 Maresins ............................................................................................................... 11 1.4.5 SPMs derived from n-3 DPA ............................................................................... 12 1.5 Protectin D1 ................................................................................................................. 14 1.5.1 Isolation and structure elucidation ....................................................................... 15 1.5.2 Further biosynthesis and metabolism ................................................................... 15 1.5.3 Syntheses of Protectin D1 .................................................................................... 18 1.6 Synthetic methods ....................................................................................................... 28 1.6.1 Z-selective Wittig reaction ................................................................................... 28 1.6.2 Sonogashira coupling reaction ............................................................................. 29 1.6.3 Evans-Nagao stereoselective aldol reaction ......................................................... 30 1.7 Aim of study ................................................................................................................ 31 1.7.1 Retrosynthetic analysis of analog 94 .................................................................... 32 1.7.2 Retrosynthetic analysis of analog 95 .................................................................... 33 2 Results and discussion ........................................................................................................ 35 2.1 Synthesis of the ω-fragment 91 ................................................................................... 35 2.1.1 Synthesis of 3-methylpent-4-yne-1,3-diol (98) .................................................... 36 2.1.2 Synthesis of 3,3,9,9-tetraethyl-5-ethynyl-5-methyl-4,8-dioxa-3,9-disilaundecane (99)…….. ......................................................................................................................... 37 2.1.3 Synthesis of 3-methyl-3-((triethylsilyl)oxy)pent-4-ynal (100) ............................ 38 2.1.4 Synthesis of (Z)-triethyl((3-methylhex-4-en-1-yn-3-yl)oxy)silane (91) .............. 40 2.2 Synthesis of the α –fragment 67 .................................................................................
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