Concise Synthesis and Their Anticancer Activity Evaluation By
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Cannogenol and Related Cardiotonic Steroids: Concise Synthesis and their Anticancer Activity Evaluation by Bijay T. Bhattarai A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in the University of Michigan 2018 Doctoral Committee: Associate Professor Pavel Nagorny, Chair Professor John Montgomery Assistant Professor Alison Narayan Professor John Wolfe Bijay T. Bhattarai [email protected] ORCID iD: 0000-0001-6972-1998 © Bijay T. Bhattarai 2018 Dedication To my mom, dad, and grandmother (You have sacrificed your happiness for the sake of mine. You have compromised so much to make sure we were well educated and more importantly, developed as good human beings. You have encouraged and inspired me to love science. Thank you for everything!) ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Pavel Nagorny for giving me the opportunity to be a part of his lab and complete my graduate studies. When I started graduate school, I wanted to work with an energetic scientist who had lots of new, brilliant, and challenging ideas, the one who would inspire me to work hard, smart, and persist through challenges that graduate school presents. Pavel was just that person. He was always around when I needed to discuss my ideas or my problems. He gave me an opportunity to pursue new ideas that we found interesting. I was also fortunate to have taken CHEM 541 (Synthesis Course for Graduate Students) with Pavel in my first year because this class was simply one of the best classes I have taken in my grad school. I want to specially thank to Dr. John Montgomery for the opportunity he gave me to rotate in his lab during my first semester which was a valuable learning opportunity and for the advices and support he gave me throughout my graduate career. I would like to thank Dr. Montgomery, Dr. John Wolfe, and Dr. Alison Narayan for serving in my committee and providing me with valuable feedback during my time in graduate school. I am grateful to all my undergraduate advisors Dr. Debra Dolliver, Dr. Jean Fotie, and Dr. Kevin Shaughnessy. You all trained me, trusted me, and pushed me to pursue a doctorate program. You will always be my inspiration. I had an amazing learning opportunity in the Nagorny Group from exceptionally talented former group members: Dr. Alina Borovika, Dr. Nathan Cichowicz, Dr. Enoch Mensah, Dr. Grace Winschel, and Dr. Brian Larsen. The thiophosphoramide project wouldn’t be possible without the iii help of Dr. Jia-Hui Tay. I would also like to thank Dr. Will Kaplan and Dr. Nathan Cichowicz for their collaboration in the steroid projects. Special shout out to a highly talented and hardworking post-doc, Dr. Hem Raj Khatri with whom I have spent countless hours discussing chemistry, seeking help, discussing about life, and fighting over soccer. Thank you for all your help with my thesis as well. I was also very fortunate to work among a group of smart chemists and I am grateful to all of them, especially my friends Jeonghyoo, Alonso, Siyuan, Zack, Sibin, Rami, and Nick. To my family, thank you for supporting me in every step of my life. I couldn’t have done any of it without your commitment towards my education and upbringing. Thank you for believing in me. And finally, I would like to thank Anuska, without whom my time in graduate school would have been an uphill battle. You have been very helpful, and particularly during this strenuous period of thesis writing. iv Table of Contents Dedication ii Acknowledgements iii List of Schemes viii List of Figures xi List of Tables xiii List of Abbreviations xiv Abstract xvi CHAPTER Chapter 1: Thiophosphoramides as Cooperative Catalysts for Copper-catalyzed Arylation of Carboxylates with Diaryliodonium Salts 1.1. Introduction…………………………………………………………………………………...1 1.2. Three Hydrogen Bond Donors………………………………………………………………..9 1.3. Anion Recognition…………………………………………………………………………..12 1.4. Thiophosphoramides as Cooperative Catalysts for Copper-catalyzed Arylation of Carboxylates with Diaryliodonium Salts ...………………………………………….………......17 1.5. Other Reactions……………………………………………………………………..……… 30 1.6. Conclusion ………………………………………………………………….....……………31 v 1.7. Experimental………………………………………………………………………......…….33 Chapter 2: Cardiac Steroids: Introduction and Previous Synthesis 2.1. Introduction………………………………………………………………………………….49 2.2. Class of Cardiotonic Steroids Based on Size of Lactone Ring………………...……………51 2.3. Previous Synthesis of Cardiotonic Steroids……………………………………...………….52 Chapter 3: Enantioselective Total Synthesis of Cannogenol-3-O-α-L-rhamnoside via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions 3.1. Introduction of Cannogenol-3-O-α-L-rhamnoside and its Anticancer Activities…………...71 3.2. Initial Objective and Proposed Synthetic Route……………………………………...……..72 3.3. New Retrosynthetic Analysis…………………………………………………………….….77 3.4. Enantioselective Total Synthesis of Cannogenol……………………………………..……..79 3.5. Enantioselective Total Synthesis of Cannogenol-3-O-α-L-rhamnoside……………….……85 3.6. Conclusion……………………………………………………………………………….….91 3.7. Experimental………………………………………………………………………….……..93 APPENDIX A ………………………………………………………………………………….126 Chapter 4: Synthesis and Structure-Activity Relationships of Cardiotonic Steroids and Their Analogs to Identify Nanomolar Inhibition Against Cancer Cell Lines 4.1. Introduction………………………………………………………………………...………148 4.2. Mode of Action of Cardiotonic Steroids…………………………………………….……..149 4.3. Cardiotonic Steroids as Anticancer Agent………………………………………..………..151 4.4. C19 Oxygenated Steroids and Their Scope in Anticancer Activities………………….…..155 4.5. Isolation of Cannogenol Based Steroids and Their Anticancer Activity………………..…157 4.6. Generation of Relevant Biological Analogs…………………………………………….…162 4.7. Total Synthesis of Cannogenol-3-O-glucopyranoside and Analog 4.42……………….….167 vi 4.8. Structure Activity Relationships (SAR) Results from Figure 4.3 ………………………...171 4.9. Cannogenol-3-O-α-L-rhamnoside as Anticancer Agent…………………………….……..174 4.10. 2nd Generation Analogs…………………………………………………………………...176 4.11. Current and Future Directions……………………………………………………………177 4.12. Experimental………………………………………………………………...……………178 vii List of Schemes Scheme 1.1. First Example of Catalytic Diels-Alder Cycloaddition Catalyzed by Organic Molecules ……………………………………………………………….…………………...……2 Scheme 1.2. Proline Catalysis in Hajos-Parris-Eder-Sauer-Wiechert Reaction ………….………2 Scheme 1.3. 1,8-Biphenylenediol as Two H-bond Donor in Catalysis ……….………………….4 Scheme 1.4. Claisen Rearrangement of Allyl Vinyl Ether Catalyzed by 1.13 …….………………4 Scheme 1.5. Diels-Alder Reaction of Cyclopentadiene with Dienophile Catalyzed by Thiourea Derivatives ….……………………………………………………………………………………5 Scheme 1.6. Asymmetric Strecker reaction catalyzed by 1.20 ….………………………….…….7 Scheme 1.7. Enantioselective Michael Reaction of Malonate and Nitroolefin Catalyzed by 1.23 .7 Scheme 1.8. Asymmetric Cyclization of Hydroxylactams Catalyzed by 1.27 and the Proposed Anion Binding …...……………………………………………………………………………….8 Scheme 1.8. Rawal’s TADOOL 1.32 in Asymmetric Catalysis …….……………………………9 Scheme 1.10. Pictet-Spengler Reaction Catalyzed by Dual Catalyst 1.39 ….……………………10 Scheme 1.11. Friedel-Crafts reaction of N-methyl indole with β-nitrosyrene ...…………………11 Scheme 1.12. New Class of Three H-bond Donors 1.46 …….………………………………….11 Scheme 1.13. HBD-based Co-catalysts for the Ionic [2 + 4] Cycloaddition and the Proposed Activation of Oxocarbenium Ion by Anion Binding …..…………………………………………14 Scheme 1.14. Mechanism of ROP Promoted by Thiophosphoramide Catalyst 1.57 ……………16 Scheme 1.15. Reactions of Diaryliodonium Salts with Nucleophiles ……………………………18 viii Scheme 1.16. Diaryliodonium Salt in Total Synthesis of (-)-epibatidine …………………….…19 Scheme 1.17. Substrate Scope …….……………………………………………………………..28 Scheme 1.18. Proposed Mechanism .…………………………………………………………….29 Scheme 1.19. Control Reaction with Co-catalyst 1.85 and 1.86 ...………………………………30 Scheme 1.20. Etherification of N-hydroxyphthalimide with diphenyliodonium salt ……………30 Scheme 2.1. Semi-synthesis of Digitoxigenin by Yoshii ………………………………………..53 Scheme 2.2. Enantioselective Total Synthesis of (+)-digitoxigenin by Nakada …………………54 Scheme 2.3. Synthesis of Key Intermediate 2.25 Towards the Synthesis of Strophanthidin ……56 Scheme 2.4. Completion of the Synthesis of Strophanthidin ……………………………………57 Scheme 2.5. Synthesis of Strophanthidin by Kočovsky’s and Coworkers ………………………59 Scheme 2.6. Substrate Scope for Enantioselective Michael Reaction …………………………..61 Scheme 2.7. Diastereoselective Steroid Formation with Unnatural Configuration ……………..62 Scheme 2.8. Selected Examples for the Diastereoselective Formation of Steroids with Natural Configuration ……………………………………………………………………………………62 Scheme 2.9. Synthesis of Key Intermediate with Pre-set Oxygenation …………………………64 Scheme 2.10. Divergent Synthesis Towards Functionalized Core from Key Intermediate ……..65 Scheme 2.11. Synthesis of Fully Oxygenated Vinyl Iodides Epimeric at C5 …………………..65 Scheme 2.12. Total Synthesis of (+)-19-hydroxysermentogenin, and (+)-Trewianin Aglycone ..66 Scheme 3.1. Oxidation Attempts to Synthesize Extended Enone 3.6 ….……………….………..73 Scheme 3.2. Formation of Natural Configuration in 6665 Ring System ……………..………….75 Scheme 3.3. Initial Route Towards the Synthesis of Cannogenol ………………………………76 Scheme 3.4. Literature Precedence and Optimization of Transposition Reaction ...…………..…77 Scheme 3.5. Development of Enantioselective Michael Reaction …..…………………………..79