Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2017 Applications of Alkynogenic Fragmentation Products Derived from Vinylogous Acyl Triflates Ron Robert Ramsubhag Follow this and additional works at the DigiNole: FSU's Digital Repository. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES APPLICATIONS OF ALKYNOGENIC FRAGMENTATION PRODUCTS DERIVED FROM VINYLOGOUS ACYL TRIFLATES By RON ROBERT RAMSUBHAG A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2017 Ron Ramsubhag defended this dissertation on August 24, 2017. The members of the supervisory committee were: Gregory B. Dudley Co-Professor Directing Dissertation James A. Frederich Co-Professor Directing Dissertation Piotr Fajer University Representative Jack Saltiel Committee Member Lei Zhu Committee Member The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements. ii This work is dedicated to my family and my fiancée who have helped me along this rigorous path of my academic career. iii ACKNOWLEDGMENTS I would like to thank Florida State University and especially everyone in the chemistry department for allowing to pursue my Ph.D. here. Everyone in the chemistry department has given me valuable advice during my academic career. I would also like to thank my committee members for being understanding during this difficult time of the year. Your discussions and advice have helped me grow greatly when coming to my research. I would like to thank my collaborators at FAMU. Thank you for your work on Neoprofen and Homo-Neoprofen. I would like to thank Dr. Zhu and his group, especially Chris Brassard. Your advice on click chemistry has helped me expand my chemistry knowledge. To my lab mates, Nick and Josh, thank you for the wonderful experience I have had in lab 5404. It has been a great pleasure working with you all. To all the undergraduates I have work with during my time at Florida State University, thank you. Nick, Jillian, James, Emily, Danni, Chelsea, Christina, Andrew J., Stephen, Misty, Andrew H. and Brooke, I wish you all the best of luck in your future endeavors. Next, I would like to thank my family. My parents are reason why I decided to go to college. Thank you for everything you have done for me. To my fiancée Ivona, thank you. I would not be here if it were not for you believing in me. You have gotten me through tough times and I am forever grateful to you. Last, but not least, I would like to thank Dr. Dudley. You have been an inspiration to me. You were always pushing me forward, and because of you, I am a better scientist today. iv TABLE OF CONTENTS List of Tables ................................................................................................................................. vi List of Figures ............................................................................................................................... vii List of Schemes ............................................................................................................................ viii Abstract ............................................................................................................................................x 1. INTRODUCTION TO “GROB-TYPE” FRAGMENTATION REACTIONS ..........................1 1.1 Introduction and Definition of Grob Fragmentation ............................................................1 1.2 History and Mechanistic Thoughts ......................................................................................2 1.3 Grob-Type Fragmentation Reactions and Their Applications .............................................6 1.4 Insight into Fragmentation Methodology Utilizing Vinylogous Acyl Triflates ................12 1.5 Synopsis Detailing Applications of Fragmentation Reactions using Vinylogous Acyl Triflates ..........................................................................................................................................14 2. ORTHOGONAL DUAL-CLICK DIYNE TO EXPLORE CLICK CHEMISTRY ..................16 2.1 Introduction to Click Chemistry ........................................................................................16 2.2 Dual Click Systems: Copper Azide-Alkyne Cycloaddition (CuAAC) vs Strained- Promoted Azide-Alkyne Cycloaddition (SPAAC) Reactions ...........................................19 2.3 Synthesis of the Dual-Click Benzocylcononyne N-propargyl Carbamate and Results .....21 2.4 Experimental Data .............................................................................................................27 3. SYNTHESIS OF NEOPROFEN AND HOMO-NEOPROFEN: RIGID ANALOGUES OF IBUPROFEN USING A TANDEM FRAGMENTATION OLEFINATION METHODOLOGY TO MODIFY THE 3-D TOPOLOGY OF PHARMACEUTICAL SUBSTANCES ....................38 3.1 Introduction to Neopentylene Ring-Fused Compounds Found in Nature .........................38 3.2 Synthesis and Preliminary Results of Neoprofen and Homo-Neoprofen ..........................40 3.3 Experimental Data .............................................................................................................46 APPENDICES ...............................................................................................................................60 A. 1HNMR AND 13CMNR SPECTROSCOPIES FOR CHAPTER 2 ...........................................60 B. 1HNMR AND 13CMNR SPECTROSCOPIES FOR CHAPTER 3 ...........................................68 C. LIST OF CHEMICAL TERMS ................................................................................................78 References ......................................................................................................................................80 Biographical Sketch .......................................................................................................................86 v LIST OF TABLES Table 1. Expansion of Vinylogous Acyl Triflates.........................................................................23 Table 2. Trials: Chemoselective Click Reactions .........................................................................25 vi LIST OF FIGURES Figure 1. Alkynogenic Fragmentation Over the Past Decades .....................................................11 Figure 2. CuAAC and Triazoles as PTP Inhibitors .......................................................................17 Figure 3. Cyclooctynes – Reactivity and Applications .................................................................18 Figure 4. Dual Click Substrates Using Strained Promoted Alkynes and Terminal alkynes with Copper Catalyst ..............................................................................................................................19 Figure 5. One-Pot Chemoselective Double-Click Reaction .........................................................20 Figure 6. 1H NMR to Determine Triazole Ratio ...........................................................................31 Figure 7. 1H NMR to Determine Triazole Ratio ...........................................................................32 Figure 8. Natural Products Found to Possess a Neopentylene Motif and Popular Pharmaceuticals .............................................................................................................................39 Figure 9. Ibuprofen and Analogues Neoprofen and Homo-Neoprofen ........................................40 Figure 10. Naproxen and Flurbiprofen .........................................................................................41 Figure 11. IBU (blue) vs. Neoprofen (green) Overlaid in the COX-2 Enzyme Pocket ................42 Figure 12. Human COX-2 Activity Inhibition Assay; activity of homoneoprofen (36, FSU2, red bar) was intermediate between that of ibuprofen (IBU, yellow bar) and neoprofen (35, FSU1, blue bar). The data represent COX-2 Activity (% Control) and are presented as the Mean ± St. Dev, n=2. Statistical difference from the controls were determined by a students t- test. *P < .05.‡................................................................................................................................................45 vii LIST OF SCHEMES Scheme 1. A General Outline of a One-Step Grob Fragmentation .................................................2 Scheme 2. Beckmann Fragmentation ..............................................................................................2 Scheme 3. History of Various Fragmentation Reactions Involving C-C Bond Cleavage...............3 Scheme 4. Mechanistic Considerations of Grob Fragmentation Reactions ....................................4 Scheme 5. Fragmentation Observations of 1,10-Decalindiol Monotosylates .................................6 Scheme 6. Synthesis of a Juvenile Hormone Using a Grob Fragmentation ....................................7 Scheme 7. Ring Expansion Using a Concerted Grob Fragmentation .............................................8 Scheme 8. Examples of Extended Fragmentation Reaction Scaffolds ............................................9 Scheme 9. Grob Fragmentations that Produce Allenes .................................................................10 Scheme 10. Eschenmoser-Tanabe Fragmentation .........................................................................11 Scheme