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Pairwise Oxidative Dearomatization and N PAIRWISE OXIDATIVE DEAROMATIZATION AND N-HYDROXYCARBAMATE DEHYDROGENATION: MOLECULAR COMPLEXITY VIA AN ACYLNITROSO DIELS–ALDER CYCLOADDITION CASCADE INSPIRED BY TETRODOTOXIN Steffen N. Good A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry. Chapel Hill 2018 Approved by: Jeffrey S. Johnson Sidney M. Wilkerson-Hill Michel R. Gagné Alexander J. M. Miller Bo Li © 2018 Steffen N. Good ALL RIGHTS RESERVED ii ABSTRACT Steffen N. Good: Development and Application of an Oxidative Dearomatization/Acylnitroso Diels–Alder Cycloaddition Cascade Toward the Total Synthesis of (±)-Tetrodotoxin (Under the direction of Jeffrey S. Johnson) I. Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin. Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. Drawing inspiration from the complex natural product tetrodotoxin, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N- hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso DielsAlder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. II. Oxidative Dearomatization/Acylnitroso Diels–Alder Cycloaddition Cascade: An Approach Toward the Total Synthesis of (±)-Tetrodotoxin Tetrodamine, a common conceptual intermediate en route to tetrodotoxin, represents a challenging synthetic target due to its densely functionalized cyclohexane core. Capitalizing on the latent functionality embedded within the benzenoid nucleus, we deploy an oxidative dearomatization/acylnitroso Diels–Alder iii cycloaddition cascade to access a highly functionalized cyclohexanone intermediate bearing structural and stereochemical features in common with tetrodamine. iv In memory of the late Jeffrey Allan Good – father, role model, best friend. v ACKNOWLEDGEMENTS Firstly, I would like to thank my family for their support. I would especially like to thank my mother, Sherry Good. We may not always agree, but I have tremendous respect for the sacrifices you have made for my brothers and I. I would certainly not be who I am today without you. I would also like to thank my older brother, Justin Good. You were a role model to me growing up and I aspired to be more like you in many ways. My interest in chemistry, and science in general, stems in part from you. I would like to thank Ashley Kretsch. You have helped me grow as a person, challenging me and providing different perspectives. Whether I had a good day or a bad day, you always made me smile. Although I am sincerely thankful for our time together spent exploring new places and new foods, I am most thankful for the little things – four years of bad jokes, walks around the neighborhood, workout dates, discussing chemistry on the bus, and impromptu Sunday debates. Simply put, you have made my graduate school experience “pretty good.” I would also like to thank the Johnson group members and alumni with whom I overlapped for helping me develop as a chemist. Whether it was helping me prepare for my preliminary candidacy exam, helping me with revisions to my manuscript/presentations, or discussing chemistry over a cold beer, feedback from the group was invaluable. I would like to especially thank Kendrick Smith, Blane Zavesky, and Jacob Robins. Kendrick Smith: for your willingness to discuss potential ideas and for being an incredible literature resource. Blane Zavesky: for helpful discussion regarding the synthesis of tetrodotoxin. Jacob Robins: for taking over the synthesis of tetrodotoxin. I have no doubt you will be able to finish it. Finally, I would like to acknowledge my PI, Jeff Johnson. I am sincerely grateful to have learned and developed under your guidance. The freedom you allow your students to explore and develop their projects fosters an atmosphere of independent learning and problem solving while your knowledge and expertise is an invaluable resource. Your practical approach to challenging/significant problems in synthetic chemistry is a constant source of inspiration. vi TABLE OF CONTENTS LIST OF TABLES.........................................................................................................................................ix LIST OF FIGURES AND SCHEMES............................................................................................................x LIST OF ABBREVIATIONS AND SYMBOLS.............................................................................................xii CHAPTER ONE HIGHLY FUNCTIONALIZED TRICYCLIC OXAZINANONES VIA PAIRWISE OXIDATIVE DEAROMATIZATION AND N-HYDROXYCARBAMATE DEHYDROGENATION: MOLECULAR DIVERSITY INSPIRED BY TETRODOTOXIN.....……………………………………………………………………1 1.1 Introduction.........................................................................................................................................…1 1.2 Background............................................................................................................................................1 1.2.1 History and Retrosynthetic Analysis of Tetrodotoxin………………………………………….1 1.3 Results and Discussion………………………………………………………………………………………...3 1.3.1 Acylnitroso Diels–Alder Cycloaddition Optimization…………………………………………..3 1.3.2 Development of a One-pot Oxidation/Acylnitroso Diels–Alder Cycloaddition………………………………………………………………………..5 1.3.3 Substrate Scope and Dienophile Facial Selectivity…………………………………………...6 1.3.4 Secondary Transformations of the [2.2.2]-cycloadducts....…………………………………..7 1.4 Conclusions ……………………………………………………………………………………………………..8 1.5 Experimental Details…………………………………………………………………………………………....8 REFERENCES……………………………………………………………………………………………………...29 CHAPTER TWO OXIDATIVE DEAROMATIZATION/ACYLNITROSO DIELS–ALDER CYCLOADDITION CASCADE: AN APPROACH TOWARD THE TOTAL SYNTHESIS OF (±)-TETRODOTOXIN...................................................32 2.1 Introduction…....……………………………………………………………………....………………...….....32 2.1.1 Previous Syntheses of Tetrodotoxin………………………………………………………......32 2.2 Synthesis of a Functionalized Benzenoid Starting Material....……………………………………...........34 2.3 Functionalization of the [2.2.2]-Bicycle Scaffold……………………………………………………………38 vii 2.3.1 Dihydroxylation of the [2.2.2]-Bicycle Scaffold...…...……………………………………......38 2.3.2 Installation of the Glycolate in the [2.2.2]-Bicycle Scaffold………………………………….39 2.3.3 Ring Opening of the Epoxide and Ketone Reduction in the [2.2.2]-Bicycle Scaffold…….42 2.3.3 Reductive N–O bond cleavage.........……………………………………………………….....43 2.4 Functionalization of the Cyclohexane Scaffold…………………………………………………………….44 2.4.1 Protection of the syn-1,2-Diol and Amine Functionality in the Cyclohexane Scaffold…...44 2.4.2 Installation of the Glycolate Functionality in the Cyclohexane Scaffold…………………...46 2.4.3 Reductive Epoxide Opening Ketone Reduction in the Cyclohexane Scaffold..................48 2.5 Conclusions………………………………………………………………………………………………........52 2.6 Experimental Details…………………………………………………………………………………………..52 REFERENCES……………………………………………………………………………………………………...72 viii LIST OF TABLES Table 1-1 Optimization of the Acylnitroso Diels–Alder Cycloaddition......……………………………....4 Table 1-2 Optimization of the One-pot Adler Oxidation/Acylnitroso Cycloaddition Protocol...............5 Table 1-3 Scope of the One-Pot Oxidative Dearomatization/Acylnitroso Cycloaddition Cascade…..5 ix LIST OF FIGURES AND SCHEMES Scheme 1-1 Synthetic Strategy for Tetrodotoxin and Proposed Pairwise Oxidation/Cycloaddition........1 Scheme 1-2 Intramolecular Installation of Nitrogen at C8a..…………………………………………..…....2 Scheme 1-3 Proposed Pairwise Oxidation/Cycloaddition Cascade………………………..…..................3 Scheme 1-4 Chemoselective Reactions of Heterocycloadducts……………………………………………7 Scheme 2-1 Intramolecular Installation of the Nitrogen at C8a……………………………………………33 Scheme 2-2 Oxidation/Cycloaddition Cascade – Development of Three Stages……………………….34 Scheme 2-3 First Generation Synthesis of Salicyl Alcohol 2.16…………………………………………..34 Scheme 2-4 Synthesis of Salicyl Alcohol 2.16 from 2,3-Dimethylphenol………………………………...35 Scheme 2-5 Synthesis of Salicyl Alcohol 2.16 from 2,3,6-Trimethylphenol……………………………...35 Scheme 2-6 Proposed Exhaustive Bromination/Hydrolysis.........…………………………………………36 Scheme 2-7 Benzylic Bromination/Acetoxylation of 2,3,6-Trimethylphenol............…...……………......36 Scheme 2-8 Second Generation Synthesis of Salicyl Alcohol 2.16……………………………...…........37 Scheme 2-9 Application of the Oxidative Dearomatization/Acylnitroso Diels–Alder Cycloaddition Toward Tetrodotoxin...…...………………………………….......38 Figure 2-1 Functional Group Manipulations Needed to Access Tetrodamine from the [2.2.2]-Bicycle Scaffold...…...……………………………………......38 Scheme 2-10 Alkene Dihydroxylation of the [2.2.2]-Bicycle Scaffold………………………………………39 Scheme 2-11 Proposed Installation of the Glycolate via Nucleophilic Addition....………………………..39
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