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Mediated Alkene Oxamidation by MIKHAIL V. GERASIMOV BS

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Mediated Alkene Oxamidation by MIKHAIL V. GERASIMOV BS Development and Synthetic Application of Iodine(III)- and Chromium(VI)-Mediated Alkene Oxamidation BY MIKHAIL V. GERASIMOV B.S., Moscow State University, 2003 THESIS Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Chicago, 2015 Chicago, Illinois Defense Committee: Duncan J. Wardrop, Chair and Advisor Donald J. Wink Tom G. Driver Justin T. Mohr Karol S. Bruzik, Medicinal Chemistry and Pharmacognosy This thesis is dedicated to my adoring family, Liudmila, Vladimir, Catherine, Elena and Alexander. ii ACKNOWLEDGMENTS I wish to express my sincerest gratitude and appreciation to my advisor Professor Duncan J. Wardrop for his guidance, advice and encouragement over the past years. I am profoundly grateful for the outstanding opportunity he has given me to work on the challenging, yet fascinating projects. I would also like to thank the members of my thesis committee, Professors Donald J. Wink, Tom G. Driver, Justin T. Mohr and Karol S. Bruzik, for their valuable time, constructive criticism and insightful suggestions. I would also like to thank Professor Donald J. Wink for his guidance on sample preparation and single crystal X-ray analysis. I would like to thank my chemistry teachers Drs. Sergey A. Maznichenko and Tatiana V. Klochkova in Krasnodar, Russia who inspired me to become a chemist. I would also like to thank my former advisors Drs. Galina A. Golubeva and Liudmila A. Sviridova at Moscow State University and Professor Aziz M. Muzafarov at Institute of Synthetic Polymer Material of RAS who introduced me to research and taught me the indispensable lab techniques. I am deeply grateful to all current and former members of the Wardrop group for their collaboration, help and friendship. It was a privilege to work with this great team of people in the excellent scientific environment. I would like to thank Dr. Dan McElheny for the invaluable learning experience I had working as NMR technician. I would like to thank Rhonda Staudohar, Silvia Solis, Pat Ratajczyk and the entire staff of the Chemistry Department for all of their help and assistance. Finally, I would like to thank my dear wife Elena and my parents Liudmila and Vladimir for their love, endless support and encouragement. MVG iii The Obstacle is the Path. Zen proverb iv TABLE OF CONTENTS CHAPTER PAGE PART ONE: DEVELOPMENT OF NEW METHODS FOR ALKENE OXAMIDATION 1. OXAMIDATION OF ALKENES 1 1.1. INTRODUCTION. ............................................................................................................ 1 1.2. RECENT ADVANCES IN INTERMOLECULAR OXAMINATION ............................................ 3 1.3. RECENT ADVANCES IN INTRAMOLECULAR OXAMINATION ........................................... 8 1.4. METAL-FREE HYPERVALENT IODINE-MEDIATED OXAMINATION PROTOCOLS ........... 11 1.5. NITRENIUM ION CHEMISTRY ....................................................................................... 13 1.6. N-ACYL-N-ALKOXYNITRENIUM IONS. ........................................................................ 22 1.7. NITRENIUM ION CHEMISTRY IN NATURAL PRODUCT SYNTHESIS ................................ 27 1.8. I(III)-MEDIATED OXAMIDATION METHODOLOGICAL STUDY ..................................... 32 1.8.1 INTRODUCTION. ........................................................................................... 32 1.8.2 PREPARATION OF UNSATURATED O-ALKYL HYDROXAMATE SUBSTRATES . 34 1.8.3 OXAMIDATION OF O-ALKYL HYDROXAMATES USING HTIB ....................... 41 1.8.4 OXAMIDATION OF O-ALKYL HYDROXAMATES USING HMIB ...................... 54 1.8.5 OXAMIDATION OF O-ALKYL HYDROXAMATES USING HPIB........................ 60 1.8.6 HYPERVALET IODINE-MEDIATED AZASPIROCYCLIZATION. ......................... 69 1.8.7 MECHANISTIC CONSIDERATIONS ................................................................. 73 1.9. Cr(VI)-MEDIATED OXOAMIDATION OF ALKENES ....................................................... 75 1.9.1 OPTIMIZATION OF REACTION CONDITIONS, SCOPE AND LIMITATIONS ......... 78 1.9.2 MECHANISTIC STUDIES ................................................................................ 86 1.10. CONCLUSIONS ............................................................................................................. 91 1.11. EXPERIMENTAL PROCEDURES ..................................................................................... 93 PART TWO: HYPERVALENT IODINE-MEDIATED INTRAMOLECULAR OXAMIDATION OF ALKENES: SYNTHESIS OF KAINIC ACID AND SYNTHETIC STUDIES TOWARDS THE MADANGAMINE AND ALSTOSCHOLARINE FAMILIES 2. FORMAL SYNTHESIS OF KAINIC ACID ...................................................................... 159 2.1. INTRODUCTION ......................................................................................................... 159 2.2. BIOLOGICAL ACTIVITY ............................................................................................. 160 2.3. BIOSYNTHESIS .......................................................................................................... 161 v TABLE OF CONTENTS (continued) CHAPTER PAGE 2.4. KAINIC ACID AS A SYNTHETIC TARGET .................................................................... 163 2.4.1 PYRROLIDINE BUILDING BLOCKS. ............................................................. 164 2.4.2 FORMATION OF C-2-C-3 BOND .................................................................. 169 2.4.3 FORMATION OF C-3-C-4 BOND .................................................................. 171 2.4.4 CYCLOADDITION ROUTES .......................................................................... 173 2.4.5 FORMATION OF C-N BOND ........................................................................ 175 2.5. RETROSYNTHETIC ANALYSIS OF KAINIC ACID ......................................................... 177 2.6. SYNTHETIC STUDIES TOWARD KAINIC ACID ............................................................ 179 2.7. CONCLUSIONS ........................................................................................................... 195 2.7. EXPERIMENTAL PROCEDURES ................................................................................... 196 3. TOWARDS THE SYNTHESIS OF THE MADANGAMINE AND ALSTOSCHOLARINE FAMILIES ................................................................................... 217 3.1. AN INTRODUCTION TO THE MORPHAN RING SYSTEM ............................................... 217 3.2. STUDIES TOWARDS THE SYNTHESIS OF THE MADANGAMINE ALKALOIDS. ............... 219 3.2.1 SYNTHETIC APPROACHES TO THE MADANGAMINES. .................................. 220 3.2.2 RETROSYNTHETIC ANALYSIS OF THE MADANGAMINES ............................. 228 3.2.3 TOWARDS THE SYNTHESIS OF THE MADANGAMINES ................................. 230 3.3. STUDIES TOWARDS THE SYNTHESIS OF THE ALSTOSCHOLARINES ............................ 239 3.3.1 INTRODUCTION. ......................................................................................... 239 3.3.2 BIOSYNTHESIS OF ALSTOSCHOLARINES ..................................................... 240 3.3.3 RECENT ALSTOSCHOLARINES SYNTHESES ................................................. 242 3.3.4 ALSTOSCHOLARINES RETROSYNTHESIS ..................................................... 244 3.3.5 MODEL STUDIES TOWARDS THE ALSTOSCHOLARINES ............................... 245 3.3.6 ENTRY TO INDOLE NATURAL PRODUCT-LIKE COMPOUNDS ....................... 247 3.4. CONCLUSIONS ........................................................................................................... 250 3.5. EXPERIMENTAL PROCEDURES ................................................................................... 251 CITED LITERATURE .............................................................................................................. 270 APPENDICES ............................................................................................................................. 287 VITA............................................................................................................................................. 308 vi LIST OF SCHEMES Scheme 1 ......................................................................................................................................... 3 Scheme 2 ......................................................................................................................................... 5 Scheme 3 ......................................................................................................................................... 5 Scheme 4 ......................................................................................................................................... 6 Scheme 5 ......................................................................................................................................... 7 Scheme 6 ......................................................................................................................................... 7 Scheme 7 ......................................................................................................................................... 8 Scheme 8 ......................................................................................................................................... 9 Scheme 9 ......................................................................................................................................... 9 Scheme 10 ......................................................................................................................................
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