City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 9-2015 Studies Toward a General Synthesis of Poly-Substituted Alpha- Hydroxytropolones Christine Marie Meck Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/1050 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones by Christine Meck A dissertation submitted to the Graduate Faculty in Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York 2015 © 2015 CHRISTINE MECK All Rights Reserved ii This manuscript has been read and accepted for the Graduate Faculty in Chemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy. Prof. Ryan P. Murelli, Ph.D ____________________ ________________________________ Date Chair of Examining Committee Prof. Brian Gibney, Ph.D. ____________________ ________________________________ Date Executive Officer Prof. Maria Contel, Ph.D. ________________________________ Prof. Shengping Zheng, Ph.D. ________________________________ Supervisory Committee THE CITY UNIVERSITY OF NEW YORK iii ABSTRACT Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones by Christine Meck Advisor: Prof. Ryan P. Murelli, Ph.D. Chapter 1: This chapter gives a brief history of α-hydroxytropolones, how they were discovered and unique properties of these substrates. Included is a background on the bioactivity of these substrates in cellular targets such as bacteria, fungi, parasites, tumors and toxicity, as well as their ability to inhibit various metallo-based enzymes. Structure activity relationships studies are reviewed on important metalloenzymes HIV-Reverse Transcriptase (RT) and Inositol monophosphatase (IMPase). Finally the chapter finishes with a synthetic overview of α-hydroxytropolones including natural product targets such as puberulic acid, puberulonic acid, β-thujaplicinol, and α-hydroxytropolone. Chapter 2: A brief review on β-hydroxy-γ-pyrone based oxidopyrylium cycloadditions will be presented as well as important oxidopyrylium cycloaddition/ring opening procedures to yield natural tropolone products. Research from the Murelli laboratory will be highlighted. This chapter will discuss a new synthetic route toward functionalized α-hydroxytropolones. A β-hydroxy-γ-pyrone intermolecular oxidopyrylium cycloaddition with a range of alkynes that was optimized to an efficient and high yielding process will be discussed. Next two ring catalyzed ring openings will be discussed; one that utilizes boron trichloride that attains α-hydroxytropolones and 7-methoxytropolones, and a triflic acid mediated sequence that yields exclusive 7-methoyxtropolones and furans. Finally, a new reaction with the oxidopyrylium species will be highlighted that shows the exchange of alcohols in these reactive species. iv Chapter 3: Chapter three describes the background on three specific medicinal targets: ANT (2”)-Ia, HIV RT RNase H, and HBV RT RNaseH and preliminary structure activity relationship studies with α- hydroxytropolones synthesized in this research are outlined. v ACKNOWLEDGEMENTS The journey of my Ph.D. was somewhat of surprise for me. At 22 years old I got married and graduated college with a degree in English literature. I could have never imagined at 32 years old and two children later, I would be graduating with a Ph.D. in chemistry. I truly believe God’s hand was at work by placing important people and circumstances in my life to bring me to this point. First, I want to thank the chemistry faculty and staff at Brooklyn College and the Graduate Center. They created a consistently positive environment and constant support system. I want to thank my Committee Members, my former member Dr. Stacey Brenner-Moyer who pushed me to pursue the Ph.D. while aligning me with my research mentor Ryan Murelli. Maria Contel who showed me a strong confident woman scientist that inspired me to feel confident in my own abilities. Shengping Zheng whose synthesis class really engrained organic chemistry in mind and who always pushed me mentally. Second, a seminal figure in my journey was my mentor Ryan Murelli. I remember first talking on the phone with Ryan about his research and joining his group before he even started. I think we both were unsure what we were getting into, but we trusted each other, and that trust led to a productive and successful relationship. He really taught me chemistry, made chemistry fun and exciting, and pushed me to be the best chemist that I could be. He believed in me no matter what, and his positive spirit helped me to overcome barriers in my life and research. I will always be grateful for him for supporting my family life, which took a great burden off my chest, and helped me to continue to finish my Ph.D. Third, I want to thank Bonnie Kruft, Ashwini Ghogare, Rico Fraboni, Josh Jones, and Goshia Frik, who have become friends for life. They have made this Ph.D. experience enjoyable and bearable. I am so grateful to have crossed paths with these amazing individuals. I want to thank my lab mates Noushad Mohd, Danielle Hirsch, Mike D’Erasmo, and Yvonne Williams for making the lab environment like a home and for their constant support in our chemistry endeavors. I want to thank Noushad Mohd for his assistance on many of the projects. His energy and dedication was an important part in the development of this chemistry. vi Next, I want to thank my mom and dad for always supporting me no matter what I wanted to do in life. They always made sure I had lots of love. My mother, as a single parent, taught me strength, courage, and hard work. Also I want to thank my grandmother Carol Signore for her teachings, love, and always being a constant force in my life. I want to give a special thank you to my mother-in-law Marilyn Allen. She sacrificed her life and time to take care of an infant during some of the toughest months, while I finished work towards my Ph.D. I will always remember this selfless act. Finally, my husband of 10 years Bill Allen deserves more praise then my words can express. He encouraged me to stick with the Ph.D. when many times I just wanted to quit. I saw his love for me as he sacrificed his time to solely take care of the boys while I worked on my thesis. He took care of our son while I was gone for a week at a time in the city to finish my research, and wanted my success in life more than his own. He is not only handsome on the outside, but inside he is truly beautiful and godly, and every day I thank God for letting us find each other in this life. He is an awesome father, husband, friend, and he is the love of my life. I want to give praise to God for his guidance on this path. Not only did I grow spiritually through this journey, but he showed me what it meant to trust him. He blessed me with my two boys, L.D. and J.D. whose presence in my life continually motivates me to do it all for them. Also I want to thank our collaborators John Tavis, John Beutler and Staurt Le Grice, and Gerry Wright. Dr. Chad Lewis and the Lewis group at Cornell for hosting me for a summer and being for gracious, supportive, and helpful. I want to thank Connie Davis for our MS data and William W. Brennessel for crystal data. Also this research would not have been possible without funding from the NIH Score Grant (SC2GM099596) and PSC CUNY (65420-00-43), Brooklyn College, and the Graduate Center. vii TABLE OF CONTENTS 1. Chapter 1: The Biology and Synthesis of α-Hydroxytropolones ................................. 1 1.1 Introduction: A Short History and Background on α-Hydroxytropolones ..... 1 1.2 Cytotoxicity of α-Hydroxytropolones ................................................................. 2 1.2.1 Antifungal Activity ...................................................................................... 2 1.2.2 Antibacterial Activity ................................................................................... 3 1.2.3 Antitumor Activity ...................................................................................... 4 1.2.4 Antimalarial Activity ................................................................................... 5 1.2.5 Toxicology Studies .................................................................................... 6 1.3 Metalloenzyme Inhibition ................................................................................... 7 1.3.1 Inositol Monophosphatase (IMPase) ........................................................ 7 1.3.2 Aminoglycoside 2”-O-adenylyltransferase [ANT(2”)] ................................ 9 1.3.3 HIV (Human Immunodeficiency Virus) Reverse Transcriptase (RT): The Ribonuclease H (RNASE H) Active Site .............................................................. 11 1.3.4 Xenotropic Murine Leukemia Virus Related Virus (XMRV) and Herpes Simple Virus (HSV) ................................................................................. 13 1.3.5 Hepatitis B Virus (HBV) RNase H ........................................................... 14 1.3.6 Phosphotidylcholine-Preferring Phospholipase C ................................... 15 1.4 Structure Activity Relationship Studies