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The University of Southern Mississippi The Aquila Digital Community Dissertations Summer 8-1-2018 Synthetic and Theoretical Studies for Cyclization Reactions to Form C-C and C-N Bonds Nicholas Jentsch University of Southern Mississippi Follow this and additional works at: https://aquila.usm.edu/dissertations Part of the Medicinal-Pharmaceutical Chemistry Commons, Organic Chemistry Commons, and the Physical Chemistry Commons Recommended Citation Jentsch, Nicholas, "Synthetic and Theoretical Studies for Cyclization Reactions to Form C-C and C-N Bonds" (2018). Dissertations. 1542. https://aquila.usm.edu/dissertations/1542 This Dissertation is brought to you for free and open access by The Aquila Digital Community. It has been accepted for inclusion in Dissertations by an authorized administrator of The Aquila Digital Community. For more information, please contact [email protected]. SYNTHETIC AND THEORETICAL STUDIES FOR CYCLIZATION REACTIONS TO FORM C-C AND C-N BONDS by Nicholas Jentsch A Dissertation Submitted to the Graduate School, the College of Science and Technology and the Department of Chemistry and Biochemistry at The University of Southern Mississippi in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Approved by: Dr. Matthew Donahue, Committee Chair Dr. Julie Pigza Dr. Douglas Masterson Dr. Vijay Rangachari Dr. Ras Pandey ____________________ ____________________ ____________________ Dr. Matthew Donahue Dr. Vijay Rangachari Dr. Karen S. Coats Committee Chair Department Chair Dean of the Graduate School August 2018 COPYRIGHT BY Nicholas Jentsch 2018 Published by the Graduate School ABSTRACT Natural product total synthesis provides an alternative method for obtaining medicinally relevant compounds in a more efficient process with higher yields than what nature can provide. Natural products pose significant synthetic challenges due to the unique heterocyclic skeletons with fused and spirocyclic ring systems. Therefore, it is paramount to develop efficient reaction methodologies targeting substructures such as cyclic ureas and spiro[4.5]decanes which are prominent among marine natural products and Lycopodium alkaloids, respectively. Presented here is a compilation of research seeking to develop synthetic methods for the construction of cyclic moieties such as those previously mentioned. The objectives that are addressed include: 1) Investigating the vinylogous enolate reactivity of phenols to undergo intramolecular para-allylation with pi-allyl palladium complexes to form functionalized spiro[4.5]decanes 2) The development of synthetic strategies for the preparation of tri-substituted quinoline scaffolds and subsequent derivatization toward establishing a library of heterocyclic candidates for HIV-1 integrase inhibition and 3) Investigating a new synthetic tool for the creation of carbon-nitrogen bonds to afford 1,2-diamines as the protected cyclic urea via vinyl sulfoxide/carbodiimide annulation and sigmatropic rearrangement. ii ACKNOWLEDGMENTS I would like to acknowledge those individuals who have provided invaluable advice and support during the past five years. First, a sincere appreciation is extended to my research mentor, Dr. Matthew Donahue for his endless investment in my development as a researcher and professional and for the many years of advice which has prepared me for the next stage in my career. Additionally, I would like to express appreciation to Dr. Julie Pigza who has also invested her time and effort whenever I requested assistance or guidance. Furthermore, I would like to thank Dr. Jacques Kessl for opening a collaborative project and for the associated financial support to make the work presented in Chapter III possible. Finally, I would like to thank Professor Dean Tantillo and his research team for opening their lab to me during the Summer of 2016. Their time spent training me to perform theoretical calculations was invaluable for my development in interdisciplinary research. iii DEDICATION This collection of research is dedicated to my grandmother, Doris Jentsch. It was your words of encouragement and your tireless dedication to my early education that guided me to the path I now take. Your love and wisdom will always remain with me. May this dissertation represent the wealth of knowledge you always told me to pursue and may it serve to honor your immense investment in my success. You are greatly missed and I will continue to live by your words of inspiration. iv TABLE OF CONTENTS ABSTRACT ........................................................................................................................ ii ACKNOWLEDGMENTS ................................................................................................. iii DEDICATION ................................................................................................................... iv LIST OF TABLES .............................................................................................................. x LIST OF FIGURES .......................................................................................................... xii LIST OF SCHEMES........................................................................................................ xiv LIST OF ABBREVIATIONS ......................................................................................... xvii CHAPTER I - INTRODUCTION ...................................................................................... 1 1.1 Natural Product Isolation .......................................................................................... 1 1.2 Total Synthesis Milestones ....................................................................................... 2 1.3 The Necessity for Cyclization Reactions .................................................................. 3 CHAPTER II - APPLICATION OF TSUJI-TROST VARIANT OF THE WINSTEIN- MASAMUNE REACTION TOWARD THE SYNTHESIS OF MAGELLANINE .......... 5 2.1 Introduction ............................................................................................................... 5 2.1.1 Cyclopiane Terpenes .......................................................................................... 5 2.1.2 Acorane Terpenes .............................................................................................. 7 2.1.3 Lycopodium Alkaloids....................................................................................... 8 2.1.4 Isolation of Magellanine and the Structure Elucidation .................................... 9 2.1.5 Prior Total Syntheses of Magellanine .............................................................. 10 v 2.2 Research Hypothesis ............................................................................................... 13 2.3 Research Design and Methods ................................................................................ 13 2.3.1 New Methodology Proposed by Our Research ................................................ 13 2.3.2 Winstein-Masamune Phenolic Dearomatization.............................................. 14 2.3.3 Tsuji-Trost Variant for Phenolic Dearomatization .......................................... 15 2.4 Results and Discussion ........................................................................................... 17 2.4.1 Preparation of the Spirocyclic Precursor ......................................................... 17 2.4.2 Synthesis of the Spiro[4.5]decane .................................................................... 18 2.4.3 Formation of the Tricyclic Core ...................................................................... 31 2.5 Future Work ............................................................................................................ 39 2.6 Summary and Conclusion ....................................................................................... 40 2.7 Experimental ........................................................................................................... 41 2.7.1 General Methods .............................................................................................. 41 2.7.1.1 Experimental Techniques.......................................................................... 41 2.7.1.2 Characterization ........................................................................................ 42 2.7.1.3 NMR Parameters ....................................................................................... 42 2.7.2 Synthesis of Intermediates ............................................................................... 43 CHAPTER III – INVESTIGATION OF SYNTHETIC STRATEGIES FOR THE DEVELOPMENT OF HETEROCYCLIC SMALL MOLECULE HIV-1 INTEGRASE INHIBITORS .................................................................................................................... 53 vi 3.1 Introduction ............................................................................................................. 53 3.1.1 The Global and National Health Issue ............................................................. 53 3.1.2 The Origins of HIV .......................................................................................... 54 3.1.3 Life Cycle of the Virus .................................................................................... 54 3.1.4 Current Available Treatments .......................................................................... 55 3.2 Research Hypothesis ..............................................................................................
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