New Chemistry of Donor-Acceptor Cycloalkanes and Studies Towards the Synthesis of Streptorubin B
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Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2016 12:00 AM New Chemistry of Donor-Acceptor Cycloalkanes and Studies Towards the Synthesis of Streptorubin B Naresh Vemula The University of Western Ontario Supervisor Prof. Brian L. Pagenkopf The University of Western Ontario Graduate Program in Chemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Naresh Vemula 2016 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Organic Chemistry Commons Recommended Citation Vemula, Naresh, "New Chemistry of Donor-Acceptor Cycloalkanes and Studies Towards the Synthesis of Streptorubin B" (2016). Electronic Thesis and Dissertation Repository. 3895. https://ir.lib.uwo.ca/etd/3895 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract and Keywords Abstract This dissertation presents two separate chapters within the broad area of synthetic organic chemistry. The first chapter describes the annelation chemistry of donor-acceptor (DA) cyclopropanes and cyclobutanes for the synthesis of heterocycles. The Yb(OTf)3-catalyzed [4+2] cycloaddition between DA cyclobutanes and nitrosoarenes facilitated the synthesis of tetrahydro-1,2-oxazines in good to excellent yields as single diastereomers. Additionally, an unexpected deoxygenation occurred with electron-rich nitrosoarenes under MgI2-catalysis that afforded pyrrolidine products. The GaCl3-catalyzed [4+2] cycloaddition of DA cyclobutanes and cis-diazenes provided hexahydropyridazine derivatives in good to excellent yields as single diastereomers. Furthermore, a procedure to make spiroketals from the [4+2] cycloaddition of spirocyclic DA cyclobutanes and aldehydes is also disclosed. Lastly, a cascade reaction of DA cyclopropanes with nitrosoarenes is discussed. The reaction results in formation of tetrahydro-1,2-oxazine instead of normal cycloadduct isoxazolidine via a tandem ring opening, elimination, and cycloaddition sequence. A detailed discussion of the results along with associated mechanisms is presented. The second chapter describes multiple strategies applied towards the synthesis of the prodigiosin alkaloid streptorubin B. The key aspect of the strategies is utilization of our group developed [3+2] cycloaddition between DA cyclopropanes and nitriles. An overview of this methodology and its application towards the synthesis of natural products is presented. Keywords donor-acceptor cyclopropane, donor-acceptor cyclobutane, annelation, annulation, cycloaddition, Lewis acid, catalysis, nitrosoarene, cis–diazene, tetrahydro-1,2-oxazine, pyrrolidine, hexahydropyridazine, spiroketal, pyrroles, streptorubin B, cascade reaction, methodology, total synthesis, thiabenzene 1-oxide. ii Co-Authorship Statement Chapter 1 involves collaborative work with Andrew C. Stevens (Ph.D. 2013), Tyler B. Schon (B.Sc. 2011), and Tristan Chidley (M.Sc. 2015). In section 1.2.1.1, Dr. Stevens and Mr. Schon were responsible for reaction discovery, optimization, and some substrate scope examples. Mr. Chidley was responsible for a major portion of the experimental of the results presented in sections 1.2.1.2 and 1.2.2. iii Dedication For my lost self iv Acknowledgments There are many great people and experiences that helped me to become who I am today. First and foremost, I am indebted to my mother Suguna Vemula, who has been my inspiration, strength, and best friend. There was a time, due to extreme poverty, that I decided to give up on studies, and it was my uneducated mother who insisted I pursue higher studies. Now, I am scared to imagine how my life would have been without education. I am grateful to my supervisor, Prof. Brian Pagenkopf for all that he has taught me over the last five years. I can most certainly say, the intellectual freedom he gave me to explore my own ideas, to write manuscripts, and present research at conferences has helped me grow as an independent researcher. He always respected and supported my (amateur) chemistry ideas, tolerated my weird work hours, and provided guidance whenever necessary, and for that I am thankful. I would like to thank, Prof. Michael Kerr, who has always been genuinely excited to discuss my chemistry ideas and related topics. From the countless discussions we had over the years, I have learned so much from him and he has had a great impact on my perception towards organic synthesis and research in general. I would like to thank my thesis examination board, Professors Kim Baines, James Wisner, Stefan France, and Mark Bernards for reading my dissertation and providing valuable feedback. My sincere gratitude to Prof. Emer. Peter Guthrie for the mechanism challenges, which helped me gain a better understanding of reaction mechanisms. I would like to thank support staff of the chemistry department, Dr. Mathew Willans (NMR), Mr. Doug Hairsine (Mass Spec), Dr. Paul Boyle (X-ray), Ms. Darlene McDonald (graduate v coordinator), and Ms. Marylou Hart (ChemBio stores) for their help and support during my tenure at Western. I would like to thank past and present members of Kerr-Kopf research family for making my time at Western more enjoyable. Especially Andrew Stevens and Polydoros Kyriacou, for their friendship and constant support. Benjamin Machin, Matthew Vriesen, and Mathew Piotrowski are specially thanked for their assistance editing this dissertation. I would also like to thank Cory Palmer, Nahed Bawakid, Geoffrey Phillips, Tristan Chidley, Tyler Day, Bryan Landschoot, Huck Grover, Joanne Curial Tejeda, Mike Emmett, and Michelle Flisar for the good times we had. I would also like to thank the undergraduate volunteers, and 4491 students I mentored, for their hard work and scientific curiosity. Finally, I would like to thank my former supervisor at DuPont, Dr. Ramakrishnan Vallinayagam, for his constant encouragement and support. vi Table of Contents Abstract and Keywords ........................................................................................................ i Co-Authorship Statement................................................................................................... iii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Table of Contents .............................................................................................................. vii List of Tables ...................................................................................................................... x List of Figures .................................................................................................................... xi List of Schemes ................................................................................................................ xiii List of Abbreviations ..................................................................................................... xviii Preface............................................................................................................................ xxiii Chapter 1. New Chemistry of Donor-Acceptor Cycloalkanes ...................................... 1 1.1 Introduction ........................................................................................................... 2 1.1.1 General Introduction to Cyclopropanes and Cyclobutanes .............................. 2 1.1.2 Donor-Acceptor Cyclopropanes ...................................................................... 2 1.1.2.1 The [3+3] Cycloaddition of Nitrones and Donor-Acceptor Cyclopropanes ........................................................................................ 4 1.1.3 Donor-Acceptor Cyclobutanes ....................................................................... 12 1.1.3.1 Seminal Reports in DA Cyclobutane Chemistry .................................. 12 1.1.3.2 Synthesis of Alkoxy-activated Cyclobutane-1,1-dicarboxylates .......... 16 1.1.3.3 Reactivity of Alkoxy-activated Cyclobutane-1,1-dicarboxylates ........ 18 1.1.3.4 Additional Cyclobutane-1,1-dicarboxylates ......................................... 23 1.2 Results and Discussion ........................................................................................ 27 1.2.1 Reactivity of Donor-Acceptor Cycloalkanes with Nitrosoarenes .................. 27 1.2.1.1 The [4+2] Cycloaddition of AACDs with Nitrosoarenes ..................... 27 vii 1.2.1.2 Cascade Reaction of Donor-Acceptor Cyclopropanes: Mechanistic Studies on Cycloadditions with Nitrosoarenes and cis-Diazenes ......... 44 1.2.2 The [4+2] Cycloaddition of AACDs with cis-Diazenes ................................ 55 1.2.3 Spiroketals from AACDs ............................................................................... 59 1.3 Conclusions and Outlook ................................................................................... 63 1.4 Experimental ....................................................................................................... 65 1.4.1 General Considerations .................................................................................. 65 1.4.2 Cycloadditions of AACDs and Nitrosoarenes