University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2015 Investigation Of A Ring Fragmentation Reaction For The yS nthesis Of Tethered Aldehyde Ynones And Medium Sized Cyclic Ynones And Ynolides Ali Bayir University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Organic Chemistry Commons Recommended Citation Bayir, Ali, "Investigation Of A Ring Fragmentation Reaction For The yS nthesis Of Tethered Aldehyde Ynones And Medium Sized Cyclic Ynones And Ynolides" (2015). Graduate College Dissertations and Theses. 427. https://scholarworks.uvm.edu/graddis/427 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]. INVESTIGATION OF A RING FRAGMENTATION REACTION FOR THE SYNTHESIS OF TETHERED ALDEHYDE YNONES AND MEDIUM SIZED CYCLIC YNONES AND YNOLIDES A Dissertation Presented by Ali Bayir 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, 2015 Defense Date: February 18, 2015 Dissertation Examination Committee: Matthias Brewer, Ph.D., Advisor Victor May, Ph.D., Chairperson José S. Madalengoitia, Ph.D. Rory Waterman, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College ABSTRACT The fragmentation of γ-silyloxy-β-hydroxy-α-diazoesters to provide tethered aldehyde ynoates was discovered and developed in Prof. Brewer’s laboratory. This reaction is a Lewis acid mediated heterolytic cleavage of the Cβ-Cγ bond of a γ- silyloxy-β-hydroxy-α-diazocarbonyl functional group array contained in a ring compound. This dissertation describes a further study of this ring fragmentation reaction and application of this fragmentation to the preparation of synthetically useful organic molecules. The purpose of this dissertation work was three fold. The first objective was to extend this ring fragmentation reaction to the synthesis of tethered aldehyde ynones by fragmenting various γ-silyloxy-β-hydroxy-α-diazo ketone compounds. The second objective was to develop a new way to make medium size rings by fragmenting fused bicyclic γ-silyloxy-β-hydroxy-α-diazo ketones. The final goal was to use this reaction to make medium size ynolides by fragmentation of fused bicyclic γ-silyloxy-β- hydroxy-α-diazo esters to provide core structures for medium-size lactones which are synthetically challenging to make using other available methods. CITATIONS Material from this dissertation has been published in the following form: Bayir, A., Brewer, M.. (2014). The fragmentation of bicyclic γ-silyloxy-β-hydroxy- α-diazolactones as an approach to ynolides. Journal of Organic Chemistry, 79 (13), 6037–6046. Tsvetkov, N.P., Bayir, A., Schneider, S., Brewer, M.. (2012). A Ring Fragmentation Approach to Medium-Sized Cyclic 2-Alkynones. Organic Letters, 14, 264–267. Bayir, A., Draghici, C., Brewer, M.. (2010). Preparation of Tethered Aldehyde Ynoates and Ynones by Ring Fragmentation of Cyclic γ-Oxy-β-hydroxy-α-diazo Carbonyls. Journal of Organic Chemistry, 75 (2), 296–302. ii ACKNOWLEDGEMENTS In the name of Allah, who has given me the strength and courage to accomplish this work, I bow my head in thanks and gratitude to Allah for all His blessings. The work presented in this dissertation would not be accomplished without the continuous support, valuable guidance, patience and encouragement of my advisor Professor Matthias Brewer. I was able to reach the finish line only through his help. In my most difficult obstacles, he always used to say” keep at it; you will solve this problem Ali”. He had always been right; eventually I could find a solution with almost all of the research problems. I thank him for all the training and support he provided. He has always been very kind and respectful with me as well as with all of his students. I enjoyed working with such an exemplary researcher. I would like to thank my committee members, Professor José S. Madalengoitia and Professor Rory Waterman for their help and advice with my research problems. I would also like to thank Professor Victor May being the chair of my dissertation committee. I am also thankful to Prof. Stephen Waters and Prof. A. Paul Krapcho for their help and guidance throughout my graduate studies. Prof. Krapcho has always been an inspiration for me with his work discipline, motivation and mind blowing questions. I am very thankful to the most helpful and the nicest past and present all Brewer group members: Cristian Draghici, Muhammad Irfan Javed, Jodi Wyman, Daniel Bercovici, Dr. Nikolay Tsvetkov, Dr. Nitin Jabre, Zhe Zhang, Olivia Hoermann, Geoffrey Giampa, Ramya Srinivasan, Sarah Cleary, Ram Chandra Dhakal and Jian Fang. I am iii especially thankful to Dr. Qiufeng Huang and Nezar Al Bataineh for sharing the same laboratory with me on my good and bad days. I would also like to thank all of the faculty, staff and past and present graduate students at UVM Chemistry department. I am specifically grateful to NMR scientist Dr. Bruce Deker, Mass Spectroscopist Bruce O’Rourke, Professor Waterman and Justin Pagano who did X-ray analyses of my compounds. I would like to thank to Andrea Lucey and Kevin Kolinich in the chemistry office and our very kind glassblower Angela Gatesy. Lastly, I’d like to express my deepest gratitude and thanks to my family and friends for their love, prayers, encouragement and continuous support throughout the years. iv TABLE OF CONTENTS Page CITATIONS ....................................................................................................................... ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix CHAPTER 1 : A GENERAL BACKGROUND ON α-DIAZOCARBONYL COMPOUNDS, FRAGMENTATION REACTIONS AND MEDIUM SIZE RING SYSTEMS........................................................................................................................... 1 1.1 α-diazo carbonyl compounds .................................................................................... 2 1.1.1 Properties of α-diazo carbonyl compounds ........................................................ 3 1.1.2 Synthesis of α-diazo carbonyl compounds ......................................................... 5 1.1.3 Reactivity of α-diazo carbonyl compounds ........................................................ 8 1.1.3.1 Reactions of α-diazo carbonyl compounds with Brönsted acids. ................ 9 1.1.3.2 Reactions of α-diazo carbonyl compounds with Lewis acids .................... 11 1.1.3.3 Aldol-type addition of metalated α-diazo carbonyl compounds with aldehydes and ketones............................................................................................ 15 1.1.4 Conclusion ........................................................................................................ 19 1.2 Heterolytic Carbon-Carbon Bond Fragmentation Reactions .................................. 20 1.2.1 Description of heterolytic carbon-carbon bond fragmentation reaction and its development .............................................................................................................. 20 1.2.2 Mechanism of heterolytic C-C bond fragmentation reactions ......................... 24 1.2.3. Types of fragmentation reactions and synthetic applications .......................... 27 1.2.4 Conclusions ...................................................................................................... 30 1.3 Medium size rings and lactones .............................................................................. 31 1.3.1. Significance of medium and large (macrocyclic) rings ................................... 31 1.3.2 Synthesis of Medium Size Rings ...................................................................... 39 1.3.3 Methods to make medium size rings ................................................................ 42 1.3.3.1 Medium rings formed via cyclization reactions......................................... 43 1.3.3.2 Ring Expansion reactions to make medium size rings .............................. 52 v 1.3.3.3 Medium rings formed via fragmentation reactions .................................... 56 1.3.4 Conclusions ...................................................................................................... 61 CHAPTER 2 : TETHERED ALDEHYDE YNONES ..................................................... 62 2.1 Ring fragmentation chemistry ................................................................................. 62 2.2 Tethered aldehyde ynones via ring fragmentation chemistry ................................. 64 2.3 Significance of tethered aldehyde ynones and synthetic utility of ynones ............. 65 2.4 Results and discussion - Tethered aldehyde ynones via a ring fragmentation reaction .......................................................................................................................... 68 2.4.1 Synthesis of γ-silyloxy-β-hydroxy-α-diazoketones as fragmentation precursors