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Expanding the Frontier of Gold-Catalyzed Cyclizations and Rational Ligand Design

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Expanding the Frontier of Gold-Catalyzed Cyclizations and Rational Ligand Design University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 5-2014 Expanding the frontier of gold-catalyzed cyclizations and rational ligand design. Deepika Malhotra University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Chemistry Commons Recommended Citation Malhotra, Deepika, "Expanding the frontier of gold-catalyzed cyclizations and rational ligand design." (2014). Electronic Theses and Dissertations. Paper 893. https://doi.org/10.18297/etd/893 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The nivU ersity of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The nivU ersity of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. EXPANDING THE FRONTIER OF GOLD- CATALYZED CYCLIZATIONS AND RATIONAL LIGAND DESIGN By Deepika Malhotra B.S., Panjab University, Chandigarh, India, 2005 M.S., Panjab University, Chandigarh, India, 2007 A Dissertation Submitted to the Faculty of the College of Arts and Sciences of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Chemistry University of Louisville Louisville, Kentucky May, 2014 EXPANDING THE FRONTIER OF GOLD- CATALYZED CYCLIZATIONS AND RATIONAL LIGAND DESIGN By Deepika Malhotra A Dissertation Approved on April 16th, 2014 by the following Dissertation Committee: ____________________________ Dr. Gerald B. Hammond Dissertation Director ____________________________ Dr. M. Cecilia Yappert ___________________________ Dr. Christine Rich ___________________________ Dr. Mark E. Noble __________________________ Dr. Mahendra K. Sunkara ii DEDICATION This dissertation is dedicated to my respected father ‘Sh. Pawan Kumar Malhotra’, mother ‘Smt. Kiran Malhotra’ and my grandparents. iii ACKNOWLEDGEMENTS I am extremely grateful to my research advisor, Dr. Gerald B. Hammond, for being an excellent and supportive mentor during my Ph.D. studies. I would like to thank him for his encouraging words on science and lessons on life, which I will remember forever. I express my deep gratitude towards the incredibly humble and intelligent Dr. Bo Xu, for guiding me throughout my doctoral work. I would also like to thank the faculty members at University of Louisville Dr. M. Cecilia Yappert, Dr. Christine Rich, and Dr. Mark E. Noble of Department of Chemistry and Dr. Mahendra K. Sunkara of the Chemical Engineering Department, Speed School for their precious input, time, and for serving in my Ph.D. thesis defense committee. I am also thankful to Dr. Michael H. Nantz for his valuable suggestions and serving in my ORP and research committee. Also, I am thankful to Dr. Neal Stolowich who has been tremendously helpful in running NMR experiments and giving valuable advice towards solving the structure of complex organic molecules, especially natural products. I would like to acknowledge the computational studies support provided by Professor Ken Houk (UCLA) and Dr. Robert Paton (Oxford University, England, formerly a postdoctoral fellow in Professor Houk’s group), described at length in Chapter 3 of this thesis. Also, I am grateful to Dr. Mark S. Mashuta for crystallographic support and Dr. William N. Richmond for technical help. iv I am thankful to various funding agencies; the National Science Foundation, the National Institute of Health, the University of Louisville for a graduate fellowship and teaching support, and the Institute of Molecular Diversity and Drug Design of the University of Louisville (IMD3) for a graduate fellowship and travel award. During the course of my doctoral work, I was fortunate to be part of a dedicated research group: Dr. Bo Xu, Dr. LePing Liu, Dr. Weibo Wang, Dr. Zhuang Jin, Dr. Jose C. Aponte, Junbin Han, Manish Kumar, Shengzong Liang, Otome Elisa, Zhichao Lu, Mallory Durham, Ebule Rene and Andrew Flach. I believe our bond of friendship will always remain intact ever after I leave the lab. Last but not the least, I would like to thank the office staff in the Chemistry Department; Sherry Nalley, Syble Bullock, Aaron Howell, and Sabrina Haug, for being so supportive and helpful. I am also indebted to Mari Mujica and Nidhi Shah for being such supportive friends and honest guides. I am thankful to all my friends at University of Louisville: Davinder, Gori, Rahul, Rohini, Radhika and Karina. It’s a true blessing to have you all in my life. I am truly thankful to my Master's adviser Dr. TejVir Singh at Panjab University, Chandigarh, India for instigating the motivation and encouraging me to pursue higher studies in the field of organic chemistry. I have a deep appreciation and sincere regards for my motivating parents, Pawan Kumar Malhotra and Kiran Malhotra without their prayers and support I would not have made it this far. I would also like to thank my wonderful husband, Neeraj Kumar for his unconditional love and being so supportive throughout. v ABSTRACT EXPANDING THE FRONTIER OF GOLD-CATALYZED CYCLIZATIONS AND RATIONAL LIGAND DESIGN Deepika Malhotra April 16th, 2014 The focus of my dissertation work is to study the gold-catalyzed intramolecular and intermolecular cyclizations involving oxonium intermediates towards the application of synthetically interesting frameworks under ambient conditions and developing a rational approach for the effective catalyst design in gold catalysis. We explored the gold- catalyzed oxygen-transfer reactions of 2-alkynyl-1,5-diketones or 2-alkynyl-5-ketoesters to furnish five-membered rings bearing a quaternary carbon tethered to a carbonyl group. The detailed mechanistic investigation on the newly proposed intramolecular [4+2] cycloaddition mechanism was performed by means of isotopic experiments and quantum chemical calculations. The reactivity of alkynylenolate was investigated in the reactions of allenic ketones and vinyl ketones which led to versatile syntheses of 2-alkynyl-1,5- diketones, 4-alkynyl-3-hydroxycyclohexones and 4-alkynylcyclohexenones. We also investigated the gold-catalyzed annulations of 2-alkynyl benzaldehyde with acyclic or cyclic vinyl ethers under very mild conditions, and successfully developed synthetically interesting dihydronaphthalenes, acetal-tethered isochromenes and bicyclo[2.2.2]octane vi derivatives often found in biologically active molecules and natural products. Although there have been numerous reviews and publications on new gold-catalyzed transformations, the development of new catalysts still relies on a hit-and-miss approach. Because the decay of the active cationic gold catalyst is the main reason for the high catalytic loading required for the majority of gold-catalyzed transformations, we developed a modular approach for effective catalyst design in gold catalysis. We discovered a new phosphine–based precatalyst that is broadly applicable and highly efficient—in the parts per million (ppm) range—at room temperature or slightly elevated temperatures (<50 oC) . The ligand was preapared in one step from readily available starting materials. vii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................... iv ABSTRACT ....................................................................................................................... vi TABLE OF CONTENTS ................................................................................................. viii LIST OF FIGURES ........................................................................................................... xi LIST OF TABLES ........................................................................................................... xiii LIST OF SCHEMES........................................................................................................ xiv Chapter 1. Introduction ....................................................................................................... 1 1.1 Background of gold catalysis .................................................................................... 1 1.2 Gold-catalyzed reactions involving gold-oxonium intermediates ............................ 3 1.2.1 Carbonyl compounds as nucleophiles ................................................................ 4 1.2.2 Ethers/epoxides as nucleophiles ........................................................................ 6 1.3 Ligand design in gold catalysis ............................................................................... 12 1.4 Outline of the dissertation: ...................................................................................... 18 Chapter 2. Gold-Catalyzed Intramolecular Oxygen Transfer Reactions of 2-Alkynyl-1,5- Diketones or 2-Alkynyl-5-Ketoesters ............................................................................... 19 2.1 Background ............................................................................................................. 19 2.2 Results and discussion ............................................................................................ 21 2.3 Summary ................................................................................................................. 36 2.4 Experimental ..........................................................................................................
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