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The Importance of Bearing Methyl APPLICATION OF ORGANOCATALYSIS TO THE SYNTHESIS OF PHARMACOLOGICAL RELEVANT SCAFFOLDS: CHIRAL β- FLUOROAMINES AND AZIRIDINES. TOTAL SYNTHESIS OF CARPANONE, POLEMANNONE B & C AND BREVISAMIDE, AND A GENERAL APPROACH FOR THE CONSTRUCTION OF AZABICYCLIC RING-CONTAINING ALKALOIDS By Olugbeminiyi Fadeyi Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry August, 2011 Nashville, Tennessee Approved: Professor Craig W. Lindsley Professor Gary A. Sulikowski Professor Lawrence J. Marnett Professor Jens Meiler To Saudat, Baby on the way, My Dad, Mum, Professor Adamson, My brother and sisters. ii ACKNOWLEGEMENTS I would like to take a few paragraphs to acknowledge and extend my gratitude to the individuals whose encouragement and guidance provided me with the support that I needed to complete the work in this dissertation, and because of whom my graduate experience has been one that I will always cherish. First and above all, I praise Almighty God, the author of my ability and the source of my strength for giving me the opportunity and diligence to accomplish this goal. It is with utmost gratitude that I acknowledge my advisor, Prof. Craig Lindsley. I have been exceedingly fortunate to have an advisor who afforded me the freedom to explore and at the same time the guidance to recover when my steps faltered. Craig fulfills every meaning of an advisor, providing both support and advice in both academic and personal matters, allowing me to find my own way when necessary but making sure that I always ended in the right direction. I would also like to thank all the members of the Lindsley Group that I have interacted with during my time at Vanderbilt. The informal support and encouragement of many friends has been indispensable, and I would like particularly to acknowledge Leslie Aldrich for her patience and kindness as a loyal friend in the lab and Nate Daniels, whose sense of humor and light-hearted spirit behooves him as a trusted companion. I also owe Kyle Emmitte, Yiu-Yin (Y- Y) Cheung, and Bruce Melancon immensely for their timely advice and solutions to problems that I encountered during the course of my research. Special thanks to Steve Townsend for being a good friend and making my experience at Vanderbilt feel closer to home. iii I am also indebted to my closest friend at Vanderbilt, Danielle Kimmel who has been like family to me. The completion of my graduate experience would not have been the same without her incomparable support, honesty and unwavering encouragement through both challenges and successes. I am forever appreciative to my parents for their confidence in me, high esteem and encouragement throughout my life and my academic endeavors. Finally to the love and light of my life, my wife Saudat who has given her unconditional support, understanding and motivation from the very beginning, I give my sincere appreciation and loving gratitude. iv TABLE OF CONTENTS Page DEDICATION ........................................................................................................ ii ACKNOWLEDGEMENTS ................................................................................... iii LIST OF TABLES ............................................................................................... viii LIST OF FIGURES ............................................................................................... ix LIST OF SCHEMES.............................................................................................. xi LIST OF ABBREVIATIONS ............................................................................ xviii Chapter I. A NEW CATALYTIC Cu(II)/SPARTEINE OXIDANT SYSTEM FOR β-β′ PHENOLIC COUPLINGS OF STYRENYL PHENOLS: SYNTHESIS OF CARPANONE AND UNNATURAL ANALOGS.........................................................................1 1.1 Introduction ............................................................................................2 1.2 Biosynthetic Proposal of Carpanone-like Natural Products ..................3 1.3 Biomimetic Synthesis of Carpanone ......................................................3 1.4 Asymmetric Copper Mediated Naphthol Coupling ...............................6 1.4.1 Asymmetric Copper Mediated Naphthol Coupling ...................7 1.5 Studies of Copper Mediated β-β′-phenolic Coupling of Styrenyl Phenols ..................................................................................10 1.5.1 Synthesis of Styrenyl Phenols ..................................................10 1.5.2 Cu(II)/t-BuNH2 Oxidative Coupling of Styrenyl Phenols .......10 1.5.3 Cu(II)/Chiral Amine Oxidative Coupling of Styrenyl Phenols .....................................................................................12 1.6 Biomimetic Total Syntheses of Polemannones B and C .....................17 1.6.1 Total Synthesis of Polemannone ..............................................18 1.6.2 Total Syntheses of Polemannones B and C .............................19 1.7 Conclusion ...........................................................................................21 References ..................................................................................................34 II. APPLICATION OF ORGANOCATALYSIS TO THE SYNTHESIS OF PHARMACOLOGICAL RELEVANT SCAFFOLDS: CHIRAL β-FLUOROAMINES AND AZIRIDINES ................................36 v 2.1 General Access to Chiral β-fluoroamines and β, β-difluoroamines via Organocatalysis ..............................................................................36 2.1.1 Fluorinated Pharmaceuticals ....................................................36 2.1.2 The Fluorine Substituent Effect ...............................................37 2.1.2.1 Metabolic Stability .............................................................38 2.1.2.2 Acidity and Basicity ...........................................................39 2.1.2.3 Prenominal Fluorine Substitution Effects ..........................40 2.1.3 General Access to Chiral β-fluoroamines and β,β-difluoroamines via Organocatalysis ..................................41 2.1.3.1 Synthesis of β-fluoroamines ..............................................42 2.1.3.2 Enantioselective Fluorination ............................................47 2.1.3.3 Catalytic Enantioselective Fluorination .............................50 2.1.3.4 Studies of Organocatalyzed Synthesis of β-fluoroamine ...52 2.2 General Access to Chiral N-alkyl Terminal Aziridines via Organocatalysis ............................................................62 2.2.1 Importance and Synthetic Utility of Aziridines .......................62 2.2.2 Nucleophilic Ring-opening Reaction .......................................64 2.2.3 Rearrangement Chemistry .......................................................67 2.2.4 Synthesis of Aziridines ............................................................67 2.2.4.1 Aziridination via Intramolecular Substitution ...................68 2.2.4.2 Aziridine Formation via Nitrene Addition to Olefins ........70 2.2.4.3 Aziridine via Addition to Imines .......................................73 2.3 Conclusion ...........................................................................................84 References ................................................................................................117 III. TOTAL SYNTHESIS OF BREVISAMIDE ...........................................123 3.1 Introduction ........................................................................................123 3.2 Biosynthesis of Ladder Polyethers .....................................................131 3.3 Isolation of Brevisamide ....................................................................133 3.4 Proposed Biosynthesis of Brevisamide ..............................................135 3.5 Other Total Synthesis of Brevisamide ...............................................136 3.6 Retrosynthetic Analysis .....................................................................149 3.7 Conclusion .........................................................................................159 References ................................................................................................178 IV. A GENERAL APPROACH FOR THE CONSTRUCTION OF AZABICYCLIC RING- CONTAINING ALKALOIDS: PROGRESS TOWARDS THE TOTAL SYNTHESIS OF STEMAPHYLLINE AND GRANDISINES A, D & G ......................................................................184 4.1 Introduction ........................................................................................184 4.2 Stemona Alkaloids .............................................................................185 4.3 Biosynthesis of Stemona Alkaloids ...................................................187 4.4 Synthetic Approach to Stemona Alkaloids ........................................188 vi 4.4.1 Azepine Formation by Staudinger-Aza-Wittig Reaction .......188 4.4.2 Azepine Formation by 7-exo-tet-cyclization .........................190 4.4.3 Azepine Formation through Intramolecular Radical Coupling ...............................................................................191 4.4.4 Azepine Formation by [4+2] Cycloaddition ..........................191 4.4.5 Azepine Formation by Ring-closing Metathesis (RCM) .......192 4.4.6 Cyclic Nitrone Strategy ..........................................................193 4.4.7 Intramolecular Schmidt Rearrangement ................................193
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