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UCC Library and UCC Researchers Have Made This Item Openly Available. Please Let Us Know How This Has Helped You. Thanks! Downlo UCC Library and UCC researchers have made this item openly available. Please let us know how this has helped you. Thanks! Title The application of aryne chemistry and use of α-diazo carbonyl derivatives in indazole synthesis with biological evaluation Author(s) Hanlon, Patricia M. Publication date 2016 Original citation Hanlon, P.M. 2016. The application of aryne chemistry and use of α- diazo carbonyl derivatives in indazole synthesis with biological evaluation. PhD Thesis, University College Cork. Type of publication Doctoral thesis Rights © 2016, Patricia M. Hanlon. http://creativecommons.org/licenses/by-nc-nd/3.0/ Item downloaded http://hdl.handle.net/10468/2546 from Downloaded on 2021-10-08T13:09:14Z THE APPLICATION OF ARYNE CHEMISTRY AND USE OF α-DIAZO CARBONYL DERIVATIVES IN INDAZOLE SYNTHESIS WITH BIOLOGICAL EVALUATION Patricia M. Hanlon, B.Sc. A thesis presented for the degree of Doctor of Philosophy to THE NATIONAL UNIVERSITY OF IRELAND, CORK Department of Chemistry University College Cork Supervisor: Dr. Stuart G. Collins Head of Department: Prof. Justin D. Holmes January 2016 Table of Chapters Acknowledgements iv Abstract vi Table of Abbreviations viii Table of Figures xv Chapter 1 Introduction 1 Chapter 2 Results and Discussion 59 Chapter 3 Experimental 226 Appendix I NCI-60 One-Dose Mean Graphs i ii DECLARATION BY CANDIDATE I hereby confirm that the body of work described within this thesis for the degree of Doctor of Philosophy, is my own research work, and has not been submitted for any other degree, either in University College Cork or elsewhere. All external references and sources are clearly acknowledged and identified within the contents. I have read and understood the regulations of University College Cork concerning plagiarism. _______________________ ___________________ Patricia M. Hanlon Date: 6th January 2016 iii iv Acknowledgements I would like to take this opportunity to thank all the people who have helped me during my academic years in UCC. First and foremost, I would like to express my deepest gratitude to my supervisor Dr. Stuart Collins for giving me the opportunity to work in his lab on an interesting research project and for his continuous support, enthusiastic encouragement, expert guidance and wisdom throughout my research. Many thanks to Dr. Dan McCarthy, Dr. Lorraine Bateman and Dr. Denis Lynch for NMR assistance; Dr. Florence McCarthy and Mick O’Shea for mass spectrometry service; Barry O’Mahony for microanalysis and Derry Kearney for the glassblowing service. I also wish to thank the chemistry department technical staff for their help, in particular Dr. Matthias Jauch for IT support, Johnny Ryan and Tony Hogan for fixing all sorts of equipment and Tina Kent in the chemical stores. I am grateful to Cork City Council for funding my studies and to the DSS and UCC+ services for providing me with tutoring work. A special thanks to Dr. Ian O’Connor, Dr. Aoife O’Sullivan, Terry Horgan, Pat O’Connell, Denis Duggan, Dr. Donnacha O’Connell, Dr. Michael Cronin and Dr. Tom O’ Mahony for their help with demonstrating over the years. Special thanks to all the members of the SGC group, both past and present, who have made my time in Lab 2.14 an enjoyable experience: Linda, Elaine, Deirdre, Naomi, Róisín, Donal, Chloe, Patrick, Laura with a special mention for Valérie and Rose who brightened up many gloomy days with their smiles and good nature. Thanks to my final year project students whom I had the pleasure of working with: Louise, Patrick and Laura. Thanks also to all the other researchers on the fourth floor of the Kane building and the second floor of the Cavanagh, especially in the 2.13 write-up area: Davy, Fiona, Kate, Mike, Jonathan, Richard, Róisín and Hiren. Thank you all for your continuing friendship, it means so much to me. I would like to thank my undergraduate demonstrators, especially Brian and Denis for peaking my interest in organic chemistry during labs by being captivating teachers and for just being genuinely great guys, I’m so glad to call v you my friends. Particular thanks to Sarah, whom I have shared my entire college experience with and could not have gotten this far without. Thank you for listening to me complain, and unintentionally entertaining me with your Norn Iron rants, for convincing me to join clubs and gyms with you (but then quitting soon after) and for proofreading; your friendship means the world to me. Thank you to Mary and Caroline for your lifelong friendship and to the ‘Dotey pets’ and ‘The Bosses’ for keeping me connected to life outside chemistry. Thanks to my wonderfully supportive extended family, especially my funny and kind-hearted aunts Anne, Trisha, Catherine and Úna. The trips away and parties provided some well-needed distraction from my studies. You’ve been a great influence and source of encouragement and advice in my life (and I appreciate that ye were going to set up a(n unnecessary) fund for me if I didn’t finish college soon!!) Thanks to my sisters: Claire for setting the educational bar high, but in a different discipline so I wouldn’t be directly competing with you! And to Susan for making sure I didn’t work too hard. Thanks to both of ye for organising weddings within a few months of each other so that I could be stressed about those instead of college work!! And I’m extremely thankful that I can be favourite aunt to Scarlett, Sasha, Tomás and Bryn, who have brought so much joy to our lives. Thanks to my brothers: Seán for always rescuing me when I have car trouble and David for making me look less bad by being another adult child still living at home. Thanks to all of ye for exacerbating my middle child syndrome! Most importantly, I would like to thank my mother, Christine, for every opportunity she has provided me with and for her unwavering support (emotional and financial), love and encouragement in everything I have ever attempted. This thesis is dedicated to you, and I hope I have made you proud. A final thank you to Mark, whose endless support, encouragement and love over the years have made this process easier, I could not have done it without you. vi Abstract This thesis outlines the synthetic chemistry involved in the preparation of a range of novel indazole compounds and details the subsequent investigation into their potential as biologically active agents. The synthetic route utilised in this research to form the indazole structure was the [3+2] dipolar cycloaddition of diazo carbonyl compounds with reactive aryne intermediates generated in situ. The preparation of further novel indazole derivatives containing different functional groups and substituents was performed by synthesising alternative 1,3- dipole and dipolarophile analogues and provided additionally diverse compounds. Further derivatisation of the indazole product was made possible by deacylation and alkylation methods. Transformation reactions were performed on alkene- containing ester side chains to provide novel epoxide, aldehyde and tertiary amine derivatives. The first chapter is a review of the literature beginning with a short overview on the structure, reactivity and common synthetic routes to diazo carbonyl derivatives. More attention is given to the use of diazo compounds as 1,3-dipoles in cycloaddition reactions or where the diazo group is incorporated into the final product. A review of the interesting background, structure and reactivity of aryne intermediates is also presented. In addition, some common syntheses of indazole compounds are presented as well as a brief discussion on the importance of indazole compounds as therapeutic agents. The second chapter discusses the synthetic routes employed towards the synthesis of the range of indazoles. Initially, the syntheses of the diazo carbonyl and aryne precursors are described. Next, the synthetic methods to prepare the indazole compounds are provided followed by discussion on derivatisation of the indazole compounds including N-deacylation, N-benzylation and ester side-chain transformation of some alkene-containing indazoles. A series of novel indazole derivatives were submitted for anti-cancer screening at the U.S National Cancer Institute (NCI). A number of these derivatives were identified as hit compounds, with excellent growth inhibition. The results obtained from biological evaluation from the NCI are provided with further results pending from the Community for Open Antimicrobial Drug Discovery. vii The third chapter details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research. viii Table of Abbreviations Å angstrom Ac acetyl AIDS acquired immune deficiency syndrome aq. aqueous Bn benzyl Boc tert-butyloxycarbonyl br s broad singlet Bu butyl BuLi n-butyllithium c centi (10-2) ºC Celsius degrees CCNSC Cancer chemotherapy national service center CDCl3 deuterated chloroform 13C NMR carbon nuclear magnetic resonance ca. circa, about CO-ADD Community for Open Antimicrobial Drug Discovery COX cyclooxygenase NMR chemical shift d doublet DCE dichloroethane DCM dichloromethane dd doublet of doublets ddd doublet of doublets of doublets DEPT distortionless enhancement by polarization transfer DMF dimethylformamide DMSO dimethylsulfoxide DNA deoxyribonucleic acid dq doublet of quartets dt doublet of triplets DTP Developmental Therapeutics Programme e.g. for example equiv. equivalent(s) ix ESI electrospray ionization Et ethyl Et2O diethyl ether ESKAPE Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter
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