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Fragmentation, Rearrangement, and C-H Insertion: Reactions of Vinyl Cations Derived from Diazo Carbonyls Sarah Elizabeth Cleary University of Vermont

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Fragmentation, Rearrangement, and C-H Insertion: Reactions of Vinyl Cations Derived from Diazo Carbonyls Sarah Elizabeth Cleary University of Vermont University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2018 Fragmentation, Rearrangement, And C-H Insertion: Reactions Of Vinyl Cations Derived From Diazo Carbonyls Sarah Elizabeth Cleary University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Organic Chemistry Commons Recommended Citation Cleary, Sarah Elizabeth, "Fragmentation, Rearrangement, And C-H Insertion: Reactions Of Vinyl Cations Derived From Diazo Carbonyls" (2018). Graduate College Dissertations and Theses. 925. https://scholarworks.uvm.edu/graddis/925 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. FRAGMENTATION, REARRANGEMENT, AND C-H INSERTION: REACTIONS OF VINYL CATIONS DERIVED FROM DIAZO CARBONYLS A Dissertation Presented by Sarah Elizabeth Cleary to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy Specializing in Chemistry October, 2018 Defense Date: June 21, 2018 Dissertation Examination Committee: Matthias Brewer, Ph.D., Advisor Teresa Ruiz, Ph.D., Chairperson José S. Madalengoitia, Ph.D. Matthew D. Liptak, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College ABSTRACT Many commercialized medicinal compounds are analogs of chemicals isolated from sources found in nature (also called natural products). However, the natural sources of these chemicals, such as plants, fungi, or insects, only offer small quantities of these bioactive agents. Thus, it is typically desirable to find ways to synthesize these products and their analogs in large quantities using cost-effective methods that also minimize the impact on the environment. It is also important to develop strategies that expedite the process of modifying the natural products, which allows medicinal chemists to determine which functional groups are enhancing or deleterious to the bioactivity. In the Brewer lab, I have investigated organic reactions and methodologies with this aim - to find ways to efficiently break and form carbon-carbon bonds, and to utilize these reactions in the total synthesis of structurally related natural products. The total synthesis of natural products is often used to showcase a methodology’s utility by applying it in a more complex structure. The Lewis acid-promoted fragmentation of γ-silyloxy-β-hydroxy-α-diazo esters to provide tethered aldehyde ynoates was discovered and developed in the Brewer lab. This methodology was extended to bicyclic systems, in which the ring-fusion bond fragmented as a way to afford 10-membered ring ynones and ynolides, which are traditionally challenging to synthesize. This work will exhibit how the fragmentation reaction that provided 10- membered ynolides has the potential to lend itself to the synthesis of several structurally related, bioactive natural products via a divergent total synthesis strategy. In addition, this dissertation will describe our discovery that modifying the diazo carbonyl precursor to a β-hydroxy-α-diazo ketone changes the course of the Lewis acid- promoted reaction. Rather than a fragmentation sequence, the compound is converted to a vinyl cation, which undergoes a rearrangement then a C-H insertion of a second vinyl cation intermediate. This transition metal-free rearrangement/C-H insertion reaction provided cyclopentenone products. The migratory aptitudes of non-equivalent substituents in the cationic rearrangement step will also be discussed. Finally, the disparate reactivities of vinyl cations derived from diazo ketone, diazo ester, and diazo amide precursors will be detailed from an experimental and computational perspective. The results underscore the fact that this rearrangement and C-H insertion reaction may eventually be an effective way to prepare complex cyclopentyl-containing structures, which are common motifs in biologically active natural products. CITATIONS Material from this dissertation has been published in the following form: Cleary, S. E., Hensinger, M. J., Brewer, M.. (2017). Remote C-H insertion of vinyl cations leading to cyclopentenones. Chemical Science, 8, 6810-6814. ii ACKNOWLEDGEMENTS There are many amazing people who made this thesis possible. First I would like to give an enthusiastic thanks to my advisor, Professor Matthias Brewer. From him, I have seen what it means to be both an intuitive and inquisitive chemist, as well as an outstandingly supportive mentor who pushes a healthy balance of challenge and encouragement, which helps us become our best and brightest selves. I feel very privileged to have studied under his advisement, and like to think I have come out a confident researcher ready to test the boundaries of chemistry thanks to him! I would like to thank my committee members, Professor José Madalengoitia and Professor Matthew Liptak, for their interest, suggestions, and support with my research over the years. Their additional perspectives have broadened the way I think about chemistry, which has been essential in moving forward with project ideas. And a very gracious thank you to my chairperson, Professor Teresa Ruiz, who has given me vital advice about this dissertation and my defense, as well as what it is like to post-doc abroad. I could not have obtained crucial data without the help of Dr. Monika Ivancic and Bruce O’Rourke, both of whom I thank for their kindness and support. I would also like to thank Angie Gatesy, who provided us with numerous pieces of glassware (in particular, a diazomethane-generating apparatus, which reduced our changes of blowing up the lab)! I could never have completed my degree without the camaraderie of my fellow group mates. I have never met a group who I can laugh so hard with, and who tolerate my particular brand of insane so gracefully. Dr. Geoffrey Giampa, Ramya Srinivasan, Nicolas Dodge, Jian Fang, Magenta Hensinger, and Evan Howard, what would I have iii done without you? I would like to give a special thank you to Magenta for working closely with me on the vinyl cation project, and sharing both the ups and downs throughout the process. And I can genuinely say I would not have gotten through graduate school in one piece without Ramya Srinivasan or Nicolas Dodge. They are the kindest, sassiest, most brilliant people I have ever worked with and their friendships have kept me sane. To my fellow graduate students: our extracurricular excursions gave me something outside of chemistry to look forward to over the years! Be it Duff hour, hiking, the annual Christmas party, hanging out at the beach, or really finding any excuse to kick back with you all was truly a pleasure. To my year: Christine, Michelle, Jonathan, Matt, Nick, Teruki, and Mona, you stellar human beings! I will always fondly remember our Secret Santa/Cunning Cupid gift exchanges and Restaurant Week feasts, and could not have asked for a better crew to go through grad school with! Finally I need to thank my family. Words really cannot express my gratitude to them. Their support has been unwavering over the years. Jack and Shelia Cleary, I would not be here without you (literally!). I have tried to embody your work ethic, strength, and ambition. Still trying! Hope it works out. And to Meghan/Meg/meggles – you keep me silly and ridiculous, and I would not have gotten through the difficult times without your help lightening the mood. This dissertation was financially supported by Award GM092870 from NIGM (a component of the NIH) and the NSF under CHE-1665113. iv TABLE OF CONTENTS Page CITATIONS ........................................................................................................................ ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES………………………………………………………………………..xi LIST OF FIGURES……………………………………………………………………..xiii LIST OF ABBREVIATIONS ........................................................................................... xv CHAPTER 1 : A GENERAL BACKGROUND ON α-DIAZO CARABONYLS, 5- AND 10-MEMBERED RINGS, CATIONIC REARRANGEMENTS, AND COMPUTATIONAL ORGANIC CHEMISTRY ............................................................... 1 1.1 α-Diazo carbonyl compounds……………………………………… ...... ……….. 2 1.1.1 Properties of α-diazo carbonyl compounds…………………………………2 1.1.2 Synthesis of α-diazo carbonyl compounds………………………………….3 1.1.2.1 Diazotization reactions…………………………………………….4 1.1.2.2 Acylation of diazomethane………………………………………..4 1.1.2.3 Diazo transfer reactions…………………………………………...6 1.1.2.4 Other preparations of α-diazo carbonyls………………………….8 1.1.3 Reactivity of α-diazo carbonyl compounds…………………………………8 1.1.3.1 Reactions with Brønsted and Lewis acids………………………...9 1.1.3.2 Reactions with metal catalysts…………………………………...11 1.1.3.3 Aldol-type reactivity with aldehydes and imines………………..16 1.2 Heterolytic carbon-carbon bond fragmentation reactions………………………..17 1.2.1 Grob-type fragmentations………………………………………………….18 1.3 Medium-sized rings ............................................................................................... 20 1.3.1 Medium-size lactone natural products and their properties ........................ 21 1.3.2 Synthesis of medium-sized lactones ........................................................... 23 1.3.2.1
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