Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones by Ming-Hsiu Yang Su
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Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones By Ming-Hsiu Yang Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chairperson Ryan A. Altman Michael D. Clift Apurba Dutta Michael F. Rafferty Jon A. Tunge Date Defended: April 26, 2017 The Dissertation Committee for Ming-Hsiu Yang certifies that this is the approved version of the following dissertation: Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones Chairperson Ryan A. Altman Date Approved: April 26, 2017 ii Abstract Ming-Hsiu Yang Department of Medicinal Chemistry, April 2017 The University of Kansas Fluorine plays an important role in drug design, because of some unique features imparted by fluorine. The incorporation of fluorine into small molecules can modulate molecular physicochemical properties, metabolic stability, lipophilicity, and binding affinity to the target proteins. However, few fluorinated molecules are biosynthesized by enzymes. This means incorporating fluorine into the molecules relies on synthetic methods. Thus, efficient synthetic strategies to access the molecules bearing a variety of privileged fluorinated moieties are important for drug discovery. Fluoroalkenes are an isopolar and isosteric mimic of an amide bond with distinct biophysical properties, including decreased H-bond donating and accepting abilities, increased lipophilicity, and metabolic stability. Moreover, fluoroalkenes can also serve as probes for conducting conformational analyses of amides. These potential applications require the development of efficient methods to access fluoroalkenes. In chapter 2, a Shapiro fluorination strategy to access peptidomimetic fluoroalkenes is demonstrated. The Shapiro fluorination reactions convert a ketone into a fluoroalkene in one or two steps. Moreover, this method uses inexpensive and readily available reagents, and no transition metals are involved in the reactions. Thus, it provides an operation-simple alternative to access fluoroalkenes in medicinal chemistry. ,-difluoroketones represent a privileged substructure in medicinal chemistry, and serves as inhibitors to many hydrolytic enzymes, such as serine and aspartyl proteases. From chapters 3 to 5, palladium-catalyzed decarboxylative methods are developed for accessing -alkyl- and -aryl-,- difluoroketones. This decarboxylative strategy overcomes two major challenges associated with alkylation reactions of ,-difluoroketone enolates. Chapter 3 demonstrates that decarboxylation regioselectively generates ,-difluoroketone enolates, which are difficult to access by base iii deprotonation. Moreover, palladium catalysis enables the coupling of the ,-difluoroketone enolate with benzylic electrophiles to form a key C()–C(sp3) bond. In chapter 4, an orthogonal catalytic system is developed for accessing linear and branched -allyl-,-difluoroketones. Two distinct mechanisms are involved in the formation of the regioisomers. Chapter 5 describes a base-mediated selective para-C–H difluoroalkylation of arenes, which represents a different strategy for para-C–H functionalization of arenes compared to the known methods. These decarboxylative coupling reactions provide structurally diverse ,-difluoroketone derivatives, and should be useful for accessing potential biological probes and therapeutics. iv Acknowledgements Six years of graduate study is not an easy thing. I feel blessed to stay in KU for my graduate career, and have enjoyable and knowledgeable life. I would like to express my deepest gratitude to many people whom I have worked with, and have received help from. Without their assistance, I would never have been able to finish my graduate study and obtain the degree. First and foremost, I would like to thank my advisor, Professor Ryan Altman, for accepting me into his lab, and providing me with a good atmosphere for doing research. His guidance in poster and oral presentation, academic writing, thinking and solving scientific problems, and engaging me in research ideals help me to become a well-educated and professional chemist. His demand on high-quality of work in all my endeavors makes me a scientist. I am grateful for his patience as I know it is very hard to instruct me, an international student whose native language is not English. I would like to thank my committee members, Professors Michael Clift, Apurba Dutta, Michael Rafferty, and Jon Tunge, for their time, support, and valuable insights. Their constructive feedback makes this dissertation much perfect. Special thanks go to Dr. Justin Douglas and Sarah Neuenswander for analyses of NMR spectroscopy and Dr. Williams Todd, Lawrence Seib, and Bob Drake for analyses of Mass spectrometry. Their support and help makes my research proceed more smoothly. I would like to thank all the people who contributed in some way to the projects included in this dissertation. To my first partner, Siddharth, thanks for the help in the Shapiro fluorination project. To Doug, thank you for the help in the allylation project of -difluoroketone enolates and useful suggestions on research. To Jordan and Niusha, thanks for working with me in the benzylation project of -difluoroketone enolates. To Dr. Francisco de Azambuja, thanks for the assistance and insightful discussion in the para-C–H difluoroalkylation project. I would like to thank the past and present group members for all of the help along the way, especially Brett for helping me solve lab related problems as well as giving useful suggestions on research and manuscript writing. v I would like to thank my classmates, Anuj, Leah, Gaurav, Sanket, Molly, Rakesh, and Cameron, for the help on classes and life. I would like to thank Huiyong, Ning, and Linqui for helping me solve daily life problems and live comfortably during my graduate study. I would like to thank group members in the laboratories of Professors Aubé, Prisinzano, Blagg, Paul, Tunge, and Clift for supporting research chemicals and lab equipment. I would like to thank my parents for their love, support, and understanding. Finally, I thank God for giving me the courage and strength to go through the good and bad times of my graduate study, and leading me on a correct track toward my goals. vi Table of Contents Chapter 1. Importance and Application of Fluorine in Drug Design 1.1 The Effect of F on Physicochemical Properties……………………………………………….………..1 1.2 The Effect of F on Lipophilicity………………………………………………………………………..5 1.3 The Effect of F on Molecular Conformations…………………………………………………………..6 1.4 The Effect of F on Metabolic or in vivo Stability……………………………………………………....9 1.5 The Effect of F on Protein-Ligand Binding Interactions…………………………………………...…13 1.6 Fluorine as a Key Component of Drugs…………………………………………………………….…15 1.7 Conclusion………………………………………………………………………………………….....17 1.8 References for Chapter 1…………………………………………………………………………...….18 Chapter 2. Preparation of Peptidomimetic Fluoroalkenes via a Shapiro Reaction 2.1 Introduction to Fluoroalkenes…………………………………………………………………………22 2.2 Literature Review to Access Fluoroalkenes………………………………………………………..…24 2.3 Shapiro Fluorination to Access Fluoroalkenes……………………..…………………..………….….38 2.4 Conclusion…………………………………………………………………………………………….47 2.5 References for Chapter 2………………………………………………………………………………48 Chapter 2 Appendix: Experimental Procedures and Spectral Analyses……………...…………………...54 Chapter 3. Palladium-Catalyzed Decarboxylative Benzylation of ,-Difluoroketone Enolates 3.1 Introduction to ,-Difluoroketones……………………………………………………………….....80 3.2 Literature Review to Access ,-Difluoroketones…………………………………………….……..83 3.3 Challenges to Access -Alkyl-,-Difluoroketones………………………………………………….89 3.4 Palladium-Catalyzed Decarboxylative Difluoroalkylation to Access -Benzyl-,-difluoroketones.90 3.5 Conclusion…………………………………………………………………………………………….98 3.6 References for Chapter 3………………………………………………………………………………99 Chapter 3 Appendix: Experimental Procedures and Spectral Analyses………..……………...………...103 Chapter 4. Ligand-Controlled Regiodivergent Palladium-Catalyzed Decarboxylative Allylation of ,-Difluoroketone Enolates 4.1 Introduction to Transition Metal-Catalyzed Decarboxylative Allylation…………………..………..156 4.2 Development to Access -Allyl-,-Difluoroketones………………………………………………158 4.3 Palladium-Catalyzed Decarboxylative Difluoroalkylation to Access -Allyl-,-difluoroketones...160 4.4 An Orthogonal Set of Palladium-Catalyzed Allylation Reactions of ,-Difluoroketone Enolates...162 vii 4.5 Conclusion………………………………………………………………………………………..….175 4.6 References for Chapter 4……………………………………………………………………………..176 Chapter 4 Appendix: Experimental Procedures and Spectral Analyses……………...………………….179 Chapter 5. Palladium-Catalyzed para-C–H Difluoroalkylation of Arenes via Decarboxylation of Benzyl ,-Difluoro--keto-esters 5.1 Introduction to Selective para-C–H Functionalization of Arenes…………………………………..227 5.2 Base-Promoted Selective para-Difluoroalkylation of Arenes…………………………………..……232 5.3 Conclusion……………………………………………………………………………………….…..246 5.4 References for Chapter 5……………………………………………………………………………..247 Chapter 5 Appendix: Experimental Procedures and Spectral Analyses…………...………………….....250 viii List of Figures Chapter 1 Figure 1.1. Effect of Fluorination on Physicochemical Properties and Applications on Drug Design….…5 Figure 1.2. Fluorine Substitution Modifies Molecular Lipophilicity…………………………………….6 Figure 1.3.