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I. Total Synthesis of (+)-Spongiolactone and Derivatives

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I. Total Synthesis of (+)-Spongiolactone and Derivatives I. TOTAL SYNTHESIS OF (+)-SPONGIOLACTONE AND DERIVATIVES ENABLING INITIAL STRUCTURE-ACTIVITY RELATIONSHIP STUDIES: DISCOVERY OF A MORE POTENT DERIVATIVE II. STUDIES TOWARD RECYCLABLE ISOTHIOUREA CATALYSTS A Dissertation by NATALIE LAURA HARVEY Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Daniel Romo Committee Members, Daniel Singleton David Bergbreiter Thomas McKnight Head of Department, Francois Gabbai December 2015 Major Subject: Chemistry Copyright 2015 Natalie Laura Harvey ABSTRACT β-lactone containing natural products are attractive targets for total synthesis and subsequent biological studies. Given the remarkable ability of this moiety to covalently inhibit specific proteins, we were drawn to spongiolactone as a synthetic target. Through our studies, the first total synthesis of this compound was achieved along with the synthesis of several derivatives. This synthesis enabled cytotoxicity studies to be carried out against a variety of cancer cell lines, with good activity observed in the human chronic myelogenous leukemia (K562) cell line. Particularly intriguing was the discovery of a more potent derivative than the natural product itself which was then modified and taken on to activity based protein profiling (ABPP) studies. The first magnetite-supported benzotetramisole (BTM) catalyst was prepared and utilized in the kinetic resolution of secondary alcohols. Overall, the selectivity factor was lower than the parent (+)-BTM (s = 48 versus s = 148, respectively), however the resulting ester was achieved in excellent enantiomeric excess, albeit with low reaction conversion. Further studies suggest an unfavorable inactivation of the catalyst taking place in the presence of uncapped magnetite. The first soluble, polymer-supported BTM catalyst was also synthesized using polyisobutylene as the support. Behavior of this catalyst system was superior to the magnetite-BTM adduct in the kinetic resolution of secondary alcohols and the conversion was efficient, providing the resolved alcohol and ester both in 90% ee which ii corresponds to a selectivity factor of 79. Preliminary studies show problems of recyclability as indicated by the drop in selectivity factor (s = 51) and increase in reaction time to 16 hours. Further studies are necessary toward recoverability and recyclability of this system. iii DEDICATION To my parents, Steve and Debra Harvey iv ACKNOWLEDGMENTS I would like to thank my advisor, Prof. Daniel Romo, for his guidance during my graduate studies. The opportunity to complete a total synthesis allowed me to grow, not only in my abilities as a chemist and in problem-solving, but also as a person through the completion of a challenging project. I also am grateful for the liberty to pursue the project involving catalyst recyclability which was a personal interest and lastly, for the opportunity to complete an internship, which opened many doors and allowed me to begin my career. I would also like to thank my committee, Prof. Daniel Singleton, Prof. David Bergbreiter, and Prof. Thomas McKnight for their support throughout my studies. I would also like to thank Prof. Singleton for his exceptional instruction in physical organic chemistry. This class was invaluable as it allowed me to develop my abilities to apply what I learned, and his dedication and time invested in the class went above and beyond most other classes. I would like to thank Sandy Manning in the graduate office for her help whenever it was needed, finding answers or pointing me in the right direction. She is an asset to this department as is Julie Zercher. I am forever indebted to past and present members of the Romo group, for their support and suggestions that always pushed me to succeed. To Rae Lynn McFarlin for beginning this time with me, for all the arrow-pushing study sessions that got us through our classes, and mostly for her friendship. I would like to thank Dr. Supakarn Chamni v (Ta) for believing in me and my ability to complete my total synthesis and for her mentorship when I began in the lab, Dr. Gang Liu and Dr. J. C. Reyes for their support and inspirations, and Dr. Morgan Shirley for encouraging me to pursue an internship position. I would also like to thank Dr. Sreekumar Vellaleth and Khoi Van for their unselfish contributions to this group and for their kindness. It was a pleasure to have them as labmates. To Dr. Omar Robles, I am thankful for his encouragement and attention to detail that taught me so much early in my studies. Lastly, I could not have completed this journey without the unwavering support and sacrifices from my parents. They taught me so much in life about the value of hard work and never stopped believing in me over these past five years, even when I doubted myself. I am so fortunate to have them in my life. vi TABLE OF CONTENTS Page ABSTRACT ....................................................................................................................... ii DEDICATION .................................................................................................................. iv ACKNOWLEDGMENTS .................................................................................................. v LIST OF FIGURES ............................................................................................................ x LIST OF TABLES ........................................................................................................... xii CHAPTER I INTRODUCTION TO SPONGIANE DITERPENOID NATURAL PRODUCTS................................................................................................................ 1 1.1 Introduction ...................................................................................................... 1 1.2 Isolation of Spongiane Diterpenoids ................................................................ 1 1.3 Selected Synthetic Studies of Spongiane Diterpenoids .................................... 4 1.4 Biological Studies of the Spongiane Diterpenoids ......................................... 14 II TOTAL SYNTHESIS OF (+)-SPONGIOLACTONE AND RELATED COMPOUNDS ......................................................................................................... 17 2.1 Introduction .................................................................................................... 17 2.1.1 Previous Studies Toward Spongiolactone .......................................... 18 2.1.2 Synthesis of β-lactones via the Intramolecular, Nucleophile Catalyzed Aldol-Lactonization (NCAL) Process ........................................ 19 2.1.3 Proposed Mechanism for the Intramolecular, Nucleophile- Catalyzed Aldol-Lactonization (NCAL) Process ........................................ 24 2.1.4 Allylzinc Reagents as a Means to Install All-Carbon Quaternary Centers ......................................................................................................... 25 2.2 Results and Discussion ................................................................................... 29 2.2.1 Synthesis of Tricyclic β-lactone Core Toward Spongiolactone and Attempted SE’ Addition ........................................................................ 29 2.2.2 Modified Retrosynthetic Analysis of (±)-Spongiolactone ................. 32 2.2.3 Development of Consistent Cyclohexenylzinc Reagent Preparation .................................................................................................. 33 vii CHAPTER Page 2.2.4 NCAL-Based Kinetic Resolution: Accessing (+)-Spongiolactone and Derivatives ............................................................ 39 2.3 Conclusion ...................................................................................................... 41 III CYTOTOXICITY STUDIES OF (+)-SPONGIOLACTONE AND DERIVATIVES: DISCOVERY OF A MORE POTENT, UNNATURAL DERIVATIVE, REGIO, BIS-EPI SPONGIOLACTONE ......................................... 42 3.1 Introduction .................................................................................................... 42 3.1.1 Targeted β-lactone Derivatives Based on Synthetic Route to Spongiolactone ............................................................................................ 44 3.1.2 Measuring Cell Viability by the MTT Assay ..................................... 45 3.2 Results and Discussion .................................................................................... 46 3.2.1 Synthesis of Derivatives ..................................................................... 46 3.2.2 Initial Screening Against Various Cancer Cell Lines ........................ 48 3.2.3 Preliminary Cytotoxicity of Spongiolactone and Derivatives ............ 50 3.3 Conclusion ....................................................................................................... 52 IV CELLULAR TARGET IDENTIFICATION OF (+)-SPONGIOLACTONE AND REGIO, BIS-EPI SPONGIOLACTONE .......................................................... 53 4.1 Introduction .................................................................................................... 53 4.1.1 Activity-based Protein Profiling (ABPP) and Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) for Cellular Protein Target Identification ....................................................................... 53 4.1.2 Synthetic Design of an Alkyne-Containing Probe ............................. 56 4.1.3 β-lactones and
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