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University of California UC Riverside UC Riverside Electronic Theses and Dissertations Title Towards a Catalytic Asymmetric Cope Rearrangement and the Synthesis and Self-Assembly of Metal-Coordinated Hosts Permalink https://escholarship.org/uc/item/4gc654st Author Moehlig, Melissa Padilla Publication Date 2013 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA RIVERSIDE Towards a Catalytic Asymmetric Cope Rearrangement and the Synthesis and Self- Assembly of Metal-Coordinated Hosts A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry by Melissa Padilla Moehlig December 2013 Dissertation Committee: Dr. Richard J. Hooley, Chairperson Dr. Catharine H. Larsen Dr. Michael C. Pirrung Copyright by Melissa Padilla Moehlig 2013 The Dissertation of Melissa Padilla Moehlig is approved: Committee Chairperson University of California, Riverside ACKNOWLEDGEMENTS Graduate school has been one of the most rewarding and yet the most exhausting and stressful times of my life. It would not have survived without the help of several people. I would like to thank Dr. Courtney Meyet, Dr. Katherine Djernes, and Yoo-Jin Ghang for their friendship and all the laughs that were necessary to keep me sane. I would like to thank Michael Young, Hou Ung, and Jay-Ar Bendo for our morning coffee breaks, they were crucial to get my day started. I would like to thank Prof. Larsen for teaching me to be independent. I would like to thank Prof. Hooley for all his guidance over the past five years. You are truly a great mentor and I don’t think I would have survived graduate school without your help and advice. I would like to thank my parents, Maria and Jose, and my brothers and sisters, Alex, Fernando, Adriana and Richard for supporting me and believing in me to succeed. I would especially like to thank Richard, Monika, Celeste, and Thomas for letting me live with them to save money to start my life and providing me with many laughs to unwind after a long, stressful day in lab. I will forever be indebted to you. Last but not least, I would like to thank my loving husband Aaron. Words cannot express how much I appreciate your love and support over these past few years. You have been there for me during the most difficult times of my life and given me the confidence I needed to come this far. iv ABSTRACT OF THE DISSERTATION Towards a Catalytic Asymmetric Cope Rearrangement and the Synthesis and Self- Assembly of Metal-Coordinated Hosts by Melissa Padilla Moehlig Doctor of Philosophy, Graduate Program in Chemistry University of California, Riverside, December 2013 Dr. Richard J. Hooley, Chairperson The Cope rearrangement has been used as the key step of many natural product syntheses but to date there is only one limited example in the literature that is capable of performing a catalytic, asymmetric variant of this reaction. The first half of this dissertation focuses on our efforts towards performing a catalytic asymmetric Cope rearrangement to access remote stereocenters. The rearrangement of 2-formyl-1,5-dienes was achieved with both Brønsted and Lewis acid catalysts. The best Lewis acid catalyst was determined to be AuCl3. As there are no examples of asymmetric Au(III) catalysis, we designed and synthesized bis-α-chiral dipyrromethanes as potential new ligands for organometallic asymmetric Cope rearrangements. This work also focuses on the design and synthesis of functionalized deep cavitands for use as biomimetic C-H oxidation catalysts. Enzymes are capable of performing site-selective oxidations by incorporating substrates in their binding pockets and selectively oxidizing the C-H bond closest in proximity to the active site of the enzyme. Cavitands are capable of selectively binding guests of the appropriate size and v shape, much like enzymes. Specifically, this work involves the synthesis of cavitands that contain deep cavities with functionalized rims that possess the ability to complex to metals such as iron or copper. These deep functionalized cavitands were found to be capable of binding amines and other small guests as well as performing unprecedented anion binding. Metal coordination was also achieved at the rims of the cavitand making these metallobound cavitands potential enzymes mimics by binding a guest in their cavities and selectively oxidizing the groups closest in proximity to the catalytic sites, i.e. the metal bound rims. vi Table of Contents Abstract ............................................................................................................................... v List of Figures ..................................................................................................................... x List of Schemes ................................................................................................................ xiii List of Tables ................................................................................................................... xvi Chapter One: Cope Rearrangement Background 1.1 Introduction ................................................................................................................. 1 1.2 Diastereoselective Cope Rearrangements ................................................................... 1 1.3 Asymmetric Amino-Cope Rearrangements ................................................................ 3 1.4 Asymmetric Aza-Cope Rearrangements ..................................................................... 4 1.5 Catalytic Asymmetric Cope Rearrangements ............................................................. 6 1.6 Hydrogen Bonding Catalysts ....................................................................................... 8 1.7 References ................................................................................................................. 12 Chapter Two: Towards a Catalytic Asymmetric Cope Rearrangement 2.1 Synthesis and Design of Cope Substrates ................................................................. 18 2.2 Rearrangement Using Protic Acids and Hydrogen Bonding Catalysts ..................... 24 2.3 Cope Rearrangement Using Lewis Acid Catalysis ................................................... 29 2.4 References ................................................................................................................. 38 Chapter Three: Background on Dipyrromethane Ligands 3.1 Introduction ............................................................................................................... 45 3.2 Dipyrrins as BODIPY Dyes ...................................................................................... 46 3.3 Metallodipyrrins as C-H Bond Amination Catalysts ................................................. 48 3.4 Dipyrromethanes as Ligands for Organometallic Catalysts ...................................... 49 3.5 Synthesis of Dipyrromethanes ................................................................................... 53 3.6 References ................................................................................................................. 55 vii Chapter Four: α-Chiral Dipyrromethanes for Asymmetric Catalysis 4.1 Design of α-Chiral Dipyrromethanes ........................................................................ 60 4.2 Synthesis of α-Chiral Dipyrromethanes .................................................................... 61 4.3 As Ligands for Organometallic Catalysis .................................................................. 66 4.4 References ................................................................................................................. 70 Chapter Five: Biomimetic Receptors and C-H oxidation Catalysts 5.1 Introduction ............................................................................................................... 72 5.2 Deep Cavitands .......................................................................................................... 74 5.3 Self-Assembly of Cavitands via Intramolecular Hydrogen Bonding ........................ 75 5.4 Self-Assembly of Cavitands via Intermolecular Hydrogen Bonding ........................ 77 5.5 Self-Assembled Cavitands via Metal Coordination .................................................. 78 5.6 Non-Haem Iron Oxygenase Biomimetic C-H Oxidation Catalysts .......................... 80 5.7 Multi-Metal Catalysts ................................................................................................ 82 5.8 References ................................................................................................................. 85 Chapter Six: Functionalized Deep Cavitands 6.1 Introduction ................................................................................................................. 92 6.2 Synthesis of Pyrazine Deep Cavitand ......................................................................... 93 6.3 Synthesis of Benzimidazole Deep Cavitands ............................................................. 97 6.4 Functionalization of Benzimidazole Deep Cavitand via Transimination ................. 102 6.5 Guest Binding Studies .............................................................................................. 104 6.6 Metal Complexation ................................................................................................. 111 6.7 References ................................................................................................................
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