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Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues Lei Miao University of New Orleans

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Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues Lei Miao University of New Orleans University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses 8-6-2009 Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues Lei Miao University of New Orleans Follow this and additional works at: https://scholarworks.uno.edu/td Recommended Citation Miao, Lei, "Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues" (2009). University of New Orleans Theses and Dissertations. 985. https://scholarworks.uno.edu/td/985 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks@UNO. It has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. The uthora is solely responsible for ensuring compliance with copyright. For more information, please contact [email protected]. Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Lei Miao B.S., Chemistry, University of Science & Technology of China, China, 2003 August 2009 To my family ii ACKNOWLEDGMENTS I would like to express my gratitude to my advisor, Professor Mark L. Trudell, for his support, guidance and encouragement during my doctoral study. His confidence and knowledge helped me to stay on track and achieve my goals. I am also grateful to Professor Bruce C. Gibb , Professor Branco S. Jursic, Professor Guijun Wang and Professor John B. Wiley for being part of my committee. I wish to thank Corinne Gibb for her kind help on the NMR all the time. I wish to thank Professor Edwin D. Stevens for the X-Ray crystallographic data. I wish to thank Professor Edwin Vedejs at the University of Michigan in Ann Arbor for the assistance during the aftermath of Hurricane Katrina. I wish to thank Johanna and Kenneth Ludema for their kindness and help when I was in Ann Arbor, Michigan. I wish to thank some of the past and present members of the Trudell group for their help and support: Dr. Liang Xu, Dr. Suhong Zhang, Dr. Shaine Cararas, Dr. Harneet Kaur, Hong Shu, April Noble, Xiaobo Gu, Andrea Forsyth, Abha Verma, Kim Slaughter and Dr. Murali Reddy. Finally, I wish to thank my lovely wife Ying Long, my family and all my friends. They have been my real inspiration and my strength to succeed in my doctoral studies. iii TABLE OF CONTENTS LIST OF TABLES.......................................................................................................................vii LIST OF SCHEMES..................................................................................................................viii LIST OF FIGURES.......................................................................................................................x ABSTRACT...................................................................................................................................xi CHAPTER 1. INTRODUCTION....................................................................................................1 1.1. Nicotinic acetylcholine receptors..............................................................................................1 1.2. Nicotinic acetylcholine receptor structure and receptor subtypes............................................2 1.3. Nicotinic acetylcholine receptor subunits.................................................................................4 1.4. Nicotinic acetylcholine receptor notable variations..................................................................5 1.5. Nicotinic acetylcholine receptor binding the channel...............................................................6 1.6. Nicotinic acetylcholine receptor opening the channel..............................................................7 1.7. Nicotinic acetylcholine receptor effects....................................................................................8 1.8. Nicotinic acetylcholine receptor regulation of desensitization.................................................8 1.9. Nicotinic acetylcholine receptor roles......................................................................................9 1.10. Nicotine...................................................................................................................................9 1.11. Epibatidine............................................................................................................................11 1.12. Half maximal inhibitory concentration (IC50).......................................................................13 1.13. Half maximal effective concentration (EC50).......................................................................15 1.14. Amphibian alkaloids.............................................................................................................16 1.15. Anabasine..............................................................................................................................18 1.16. Noranabasamine....................................................................................................................19 1.17. Gephyrotoxin........................................................................................................................21 1.18. References.............................................................................................................................22 iv CHAPTER 2. Hydroxyarylketones via Regioselective Ring-Opening Reactions of Lactones with Aryllithium Reagents.....................................................................................................................27 2.1. Abstract...................................................................................................................................27 2.2. Introduction.............................................................................................................................27 2.3. Results and discussion............................................................................................................28 2.4. Conclusion..............................................................................................................................33 2.5. Acknowledgment....................................................................................................................33 2.6. Experimental section...............................................................................................................33 2.7. References...............................................................................................................................44 CHAPTER 3. Enantioselective Syntheses of Both Enantiomers of Noranabasamine..................46 3.1. Abstract...................................................................................................................................46 3.2. Introduction.............................................................................................................................47 3.3. Results and discussion............................................................................................................48 3.4. Conclusion..............................................................................................................................58 3.5. Acknowledgment....................................................................................................................58 3.6. Experimental section...............................................................................................................59 3.7. References and notes...............................................................................................................70 CHAPTER 4. A Formal Synthesis of (+)-Gephyrotoxin-Kishi’s Intermediate.............................73 4.1. Abstract...................................................................................................................................73 4.2. Introduction.............................................................................................................................73 4.3. Results and discussion............................................................................................................76 4.4. Conclusion..............................................................................................................................82 4.5. Acknowledgment....................................................................................................................83 4.6. Experimental section...............................................................................................................83 4.7. References...............................................................................................................................92 v CHAPTER 5. First Multi-gram Preparation of SCP-123, A Novel Water Soluble Analgesic........................................................................................................................................94 5.1. Abstract...................................................................................................................................94 5.2. Introduction.............................................................................................................................95 5.3. Results and discussion............................................................................................................96
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