Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2009 Organic Synthesis and Methodology Related to the Malaria Drug Artemisinin Douglas Aaron Engel Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES ORGANIC SYNTHESIS AND METHODOLOGY RELATED TO THE MALARIA DRUG ARTEMISININ By DOUGLAS A. ENGEL A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Summer Semester, 2009 The members of the committee approve the dissertation of Douglas A. Engel defended on June 30th, 2009. __________________________________ Gregory B. Dudley Professor Directing Dissertation ___________________________________ Thomas Keller Outside Committee Member __________________________________ Marie Krafft Committee Member __________________________________ Lei Zhu Committee Member __________________________________ Geoffery Strouse Committee Member Approved: _____________________________________ Joesph Schlenoff, Chair, Department of Chemistry The Graduate School has verified and approved the above-named committee members. ii This manuscript is dedicated to my family and friends who have supported me through out my life. iii ACKNOWLEDGMENTS Academically, I could not have achieved what I have without the guidance of Dr. Gregory Dudley. It the early years, he was an invaluable source of information and gave me the opportunity to work on some amazing projects. The reactions course he taught my first year in graduate school was probably the most educational course I have ever taken. In the later years, despite my protests, he has forced me to draw my own conclusions and rarely relinquishes an answer to a question I am capable of determining the answer to. I am truly appreciative of this forced evolution from a graduate student to an independent scientist. On the personal level, I have too many thank yous to include in this short acknowledgements page. So thank you to everyone who has bettered my life over the last 5 years. This includes my family who has always supported me, whether they agreed with me or not, and one of the best group of friends one could ask for. So thank you; Mom, Dad, Tiffany, Sean, Van, Shawn, Sam, and everyone else. Financially, I have to thank my mother once again. Her answer was always ―just put it on the credit card.‖ I am guessing she has her eye on some sweet rewards program prize and is just using me to get ever closer to obtaining the coveted pink American Express embroidered teddy bear. Seriously, I am truly appreciative. I also have to thank the Bovay Foundation and the MDS Research Foundation whose financial support made life on the meek graduation stipend a little more bearable. In addition, the completion of this manuscript would have been impossible without the army of editors that so graciously agreed to proofread this document. They include Dr. Mark Kearley, Sami Tlias, Kerry Gilmore, Mike Rosana, and Cece O’Leary. Special thanks go to my sister Tiffany Harris who agreed to proofread a document in a foreign language, and Dave Jones and Dr. Dudley who edited the entire document. iv TABLE OF CONTENTS List of Tables ................................................................................ v List of Figures ............................................................................... vi Abstract .................................................................................... x 1. Total Synthesis of (+)-Dihydro-epi-deoxyarteannuin B and Related Studies ........................................................................ 001 Chapter 1: History of Malaria ..................................................... 001 Chapter 2: Artemisinin: The Last Line of Defense Against Malaria .................................................................... 011 Chapter 3: Synthesis of (+)-Dihydro-epi-deoxyarteannuin B and ()-Dihydroartemisinic Acid…………………….. 020 Chapter 4: Experimental: (+)-Dihydro-epi-deoxyarteannuin B... 038 2. The MeyerSchuster Reaction and Beyond .............................. 094 Chapter 5: Evolution of the MeyerSchuster Reaction .............. 094 Chapter 6: Lewis Acid-Catalyzed MeyerSchuster Reactions: Methodology for the Olefination of Aldehydes and Ketones .................................................................. 114 Chapter 7: MeyerSchuster Experimental……………………… 144 REFERENCES ............................................................................. 224 BIOGRAPHICAL SKETCH ............................................................. 241 v LIST OF TABLES Table 1: Allylation of Menthone and Silyloxymenthone 43 ........................ 028 Table 2: Mo-Au Combo Catalysis for Rearrangement of E into α,-unsaturated Ketones F ......................................................... 101 Table 3: Selected Examples of [(ItBu)AuCl]/AgSbF6 Catalyzed Rearrangement ........................................................................... 106 Table 4: Solvent Screening With AuCl3 Catalyst ....................................... 118 Table 5: Screening of Water Equivalents .................................................. 119 Table 6: Catalyst Loading ......................................................................... 120 Table 7: Initial Screening of Substrates Using Oxygen Activated Alkynes 124 Table 8: Catalyst Loading and Optimization .............................................. 124 Table 9: Olefination of Hindered Ketones ................................................. 126 Table 10: Temperature Effect on (E/Z)-Selectivity .................................... 127 Table 11: MeyerSchuster Reaction of Ethoxyalkynyl Carbinols .............. 128 Table 12: Screening Alternative Catalysts ................................................ 133 Table 13: Effect of Additives ..................................................................... 134 Table 14: Ethoxy Acetylene Addition ........................................................ 135 Table 15: Scandium and Copper Rearrangements ................................... 136 Table 16: Two-Stage Olefination of Ketones and Aldehydes .................... 138 Table 17: Incorporation of External Alcohol Additive ................................. 142 vi LIST OF FIGURES Figure 1: Estimated Incidence of Malaria per 1000 Population, 2006........ 002 Figure 2: Global Distribution of Per Capita GDP ....................................... 003 Figure 3: Overview of Antimalarial Drugs .................................................. 005 Figure 4: Plasmodium falciparum Cycle Within Humans ........................... 006 Figure 5: Model For Formation of the Non-Covalent Heme-Chloroquine Complex .................................................................................... 007 Figure 6: Global Status of Resistance to Chloroquine and Sulphadoxine/ pyrimethamine, the Two Most Widely Used Antimalarial Drugs. 008 Figure 7: The Structure of Artemisinin and its Derivatives ......................... 008 Figure 8: General Reactivity of Artemisinin After Reductive Activation of The Endoperoxide Function ....................................................... 009 Figure 9: Artemisinin and Related Compounds ......................................... 011 Figure 10: Artemisinin is a Natural Product Extracted from Artemisia annua or Sweet Wormwood ................................................................ 012 Figure 11: Schematic Representation of the Engineered Artemisinic Acid Biosynthetic Pathway in S. cerevisiae ...................................... 015 Figure 12: Early Approaches Toward Artemisinin ..................................... 016 Figure 13: Construction of the Schmid and Hofheinz Singlet Oxygen Precursor 17 ............................................................................ 017 Figure 14: Schmid and Hofheinz End Game Strategy ............................... 017 Figure 15: First Example of Dihydroartemisinic acid 21 being converted into Artemisinin 1 ..................................................................... 018 Figure 16: Our Proposal for Generating the Key Endoperoxide ................ 019 Figure 17: Our Synthetic Targets .............................................................. 020 vii Figure 18: Eq (1) Ravindranathan Intramolecular Diels-Alder, Eq (2) Meinwald Intramolecular Diels-Alder ....................................... 021 Figure 19: Avery and Co-Workers’ Strategy to Avoid Epimerization.......... 021 Figure 20: Electrocyclic Stategies to the Decalin Ring System ................. 022 Figure 21: Other Approaches Towards the Decalin Ring System ............. 023 Figure 22: Our Retro-Synthetic Analysis ................................................... 024 Figure 23: The StorkJung Vinylsilane ..................................................... 024 Figure 24: The Original Synthesis of the StorkJung Vinylsilane .............. 025 Figure 25: Early Modifications of the StorkJung Synthesis ...................... 026 Figure 26: Dudley Lab Succint Method for Preparation of StorkJung Vinylsilane 16 ........................................................................... 026 Figure 27: Hydroboration of Bulk Isopulegol vs. Pure Isopulegol .............. 027 Figure 28: Conversion of Diol 56 to Ketone 43 ......................................... 027 Figure 29: Vinyl Addition to Silyloxymenthone 59 ..................................... 029