California State University, Northridge Towards The

CALIFORNIA STATE UNIVERSITY, NORTHRIDGE TOWARDS THE SYNTHESIS OF DIANDRAFLAVONE A thesis submitted in partial fulfillment of the requirements For the degree of Master of Science in Chemistry By Christine Ani Dimirjian August 2015 The thesis of Christine Ani Dimirjian is approved by: _______________________________________ ___________________ Dr. Daniel Curtis Date _______________________________________ ___________________ Dr. Yann Schrodi Date _______________________________________ ___________________ Dr. Thomas G. Minehan, Chair Date California State University, Northridge ii ACKNOWLEDGEMENTS I would like to express my deepest gratitude to Dr. Thomas Minehan for giving me the opportunity to work as part of his laboratory group. From my first organic chemistry lecture taught by Dr. Minehan, it was easy to see his genuine enthusiasm for the subject, which is only magnified in the laboratory. Thank you for your patience and understanding when experiments failed, and giving me encouragement to keep going with a different approach. I also thank my thesis committee, Dr. Daniel Curtis and Dr. Yann Schrodi for their feedback and input on this work. Thank you Dr. Curtis for all the support you have shown me during my time at CSUN. Thank you Dr. Schrodi for being present at the Graduate Recruitment event, it was only after talking with you during lunch that I even considered applying to the program. A thank you to past members of the Minehan group, especially Akop Yepremyan, Miran Mavlan and Xiao Cai, for paving the way for the chemistry serving as a foundation for my project. Thank you to current members who come in on a regular basis and keep the research alive. Thank you to the Chemistry Department faculty and staff. A special thank you to Dr. Simon Garrett for his encouragement to continue on in my academic career. Thank you to Irene, Sonia and Riccia in the Chemistry Office who help keep the department running! Thank you Dr. Karin Crowhurst as the graduate coordinator, Dr. Mike Kaiser for help with the NMR, and the Chemistry Stockroom for their efficient fullfillment of orders. iii DEDICATION I would like to dedicate this work to my parents who have been supportive of me throughout my academic career. I am so thankful for the value they have placed on education and providing us with all the resources my sister and I need so that we may continue in our studies. My father fueled my interest and curiosity in seeing how things work by allowing me to help fix things around the house. My mother always pushed me to stand up for myself and demand my rights. Most of all, they have shown me how to use my strengths to help others. It is their kindness and willingness to help others with no expectation or desire of repayment that makes me admire them the most and is something I hope to be able to do now and in the future. To my sister and younger cousins, hard work and patience will pay off. Follow your passions and chase your dreams. iv TABLE OF CONTENTS Signature Page…………………………………………………………………………….ii Acknowledgements…………………………………………………………………...….iii Dedication………………………………………………………………………………...iv List of Figures………………………………………………………………………...….vii List of Schemes…………………………………………………………………………viii List of Tables…………………………………………………………………………..….x List of Equations………………………………………………………………….………xi List of Abbreviations………………………………………………………..…...……...xii Abstract…………………………………………………………………………….....…xiv CHAPTER 1: CHEMICAL AND BIOLOGICAL SIGNIFICANCE OF C-ARYL GLYCOSIDES AND FLAVONES 1.1 Introduction………………………………………………………………..1 1.2 Flavones…………………………………………………………………...2 1.3 C-Aryl Glycosides………………………………………………………...9 1.4 DNA Interaction………………………………………………………….13 CHAPTER 2: METHODOLOGY IN C-GLYCOSIDE SYNTHESIS 2.1 Introduction………………………………………………………………15 2.2 Electrophilic Substitutions……………………………………………….15 2.3 Nucleophilic Addition to Electrophilic Aromatics………………………22 2.4 Transition Metals………………………………………………………...23 2.5 Examples of C-Aryl Glycoside Synthesis………………………….…...29 v CHAPTER 3: METHODOLOGY IN FLAVONE SYNTHESIS 3.1 Introduction………………………………………………………………36 3.2 Synthesis of C-Glycosylflavonoids………………………………………36 3.3 Cyclization……………………….………………………………………39 CHAPTER 4: SYNTHESIS OF DIANDRAFLAVONE 4.1 Introduction………………………………………………………………41 4.2 Structure and Retrosynthetic Analysis ……………………….….………41 4.3 Glucose moiety and first coupling……………………………….………42 4.4 Galactose Sugar Manipulations………………………………….………48 4.5 Preparation of the Chromophore .……………………………….………50 4.6 Model System for Chromophore Cyclization…………….…….…...…..54 CHAPTER 5: CONCLUSION …………………………………….……………………57 CHAPTER 6: EXPERIMENTAL ………………………………………………………58 REFERENCES………………………..…………………………………………………77 APPENDIX………………………..…………….……………………………………….83 vi LIST OF FIGURES Figure 1.1 The C-aryl Glycoside Kidamycin Figure 1.2 Flavonoid Core Figure 1.3 Flavonoid Classes Figure 1.4 Strucutres of Apigenin and Diandraflavone Figure 1.5 Kidamycin and the C10 Epimer, Isokidamycin Figure 1.6 Interaction of pluramycin and DNA backbone Figure 2.1 Oxocarbenium Ion Attack Figure 2.2 β-selective Mechanism of Trichloroacetimidates Figure 2.3 O→C Rearrangement Figure 2.4 Ferrier Rearrangement Figure 2.5 Orbitals Used During π-Complexation Figure 2.6 Glycosylation via Stannylation Figure 2.7 β-C-Glycosides from α Attack Figure 2.8 Dexcarboylative Coupling Figure 4.1 Diandraflavone Figure 4.2 Coupling of Chromophore vii LIST OF SCHEMES Scheme 1.1 Flavonoid Oxidation Scheme 1.2 Biosynthesis of Flavones Scheme 1.3 General Enzyme Degradation Mechanism Scheme 2.1 O→C Rearrangement in Vineomycinone B2 Methyl Ester Scheme 2.2 Lactone Mechanism Scheme 2.3 Reductive Aromatization Scheme 2.4 Mechanism of Palladium Mediated Glycosylation Scheme 2.5 Total Synthesis of Salmochelin SX Scheme 2.6 Organoindium Mediate Cross-Coupling Scheme 2.7 Diels-Alder Pathway to C-Aryl Glycosides Scheme 2.8 Regioselective Cycloadducts Using Silicon Tether Scheme 2.9 Palladium Catalyzed Ring Opening Scheme 2.10 Synthesis of Galtamycinone Scheme 2.11 O→C Glycoside Rearrangement for Bis-C-Glycosyl Synthesis Scheme 2.12 Synthesis of Isokidamycin Scheme 3.1 Fries-Type Rearrangement Scheme 3.2 O→C glycoside Rearrangement Scheme 3.3 Regioselective Rearrangement of Glycosyl Moiety Scheme 3.4 Cyclization via Baker-Venkataraman Rearrangement Scheme 4.1 Retroanalysis of Diandraflavone Scheme 4.2 Synthesis of Glucolactone Scheme 4.3 Sonagshira Palladium Cross-Coupling viii Scheme 4.4 Coupled Sugar Lactone and Phenylacetylene Scheme 4.5 Synthesis of Galactopyranose 6g Scheme 4.6 One-Pot Cyclization via Carbonylation Scheme 4.7 Preparation of Chromophore Through Selective Methylation Scheme 4.8 Two-step preparation of Chromophore Scheme 4.9 Model Cyclization ix LIST OF TABLES Table 1.1 Classification of C-Aryl Glycosides Table 4.1 Reaction Conditions for Lactol Reduction x LIST OF EQUATIONS Equation 3.1 Oxidative Cyclization of a Chalcone xi LIST OF ABBREVIATIONS Ac acetyl aq aqueous BF3•OEt2 boron trifluoride etherate Bn benzyl BnBr benzyl bromide d doublet DBU 1,8-Diazabicycloundec-7-ene DCM dichloromethane DIPEA diisopropyl ethyl amine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DNA deoxyribonucleic acid equiv equivalent Et2O diethyl ether Et3N triethylamine EOM ethyl methyl ether EtOH ethanol imid. imidazole iPr3SiH triisopropyl silane m multiplet MeOH methanol xii mL milliliter mmol millimole nBuLi n-butyllithium NMR nuclear magnetic resonance Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) dichloride Ph Phenyl POCl3 phosphoryl chloride PPh3 triphenylphosphine p-TsOH para-toluenesulfonic acid pyr pyridine q quartet Rf retention factor rt room temperature s singlet t triplet TBAF tetrabutyl ammonium fluoride TBAI tetrabutylammonium iodide TBS tert-butyldimethylsilyl THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMSOTf trimethylsilyl trifluoromethanesulfonate TsCl 4-toluenesulfonyl chloride TTMSS tris(trimethylsilyl)silane TTN thallium (III) nitrate xiii ABSTRACT Towards the Synthesis of Diandraflavone By Christine Ani Dimirjian Master of Science in Chemistry Diandraflavone is a natural product isolated and characterized from the Drymaria diandra plant native to Taiwan. It has been used in traditional medicine to treat a wide range of ailments from fevers to cancers. Considering the inefficient and cumbersome process of isolating diandraflavone, a synthetic route to the C-glycoside flavanoid is designed. The structure of diandraflavone shows potential for antitumor and antibacterial applications through DNA interactions. First, diandraflavone consists of two carbohydrate moieties on opposite sides of the molecule, one derived from glucose and the other from galactose, both of which contribute to DNA binding specificity. Second, a flavone chromophore (derived from an aromatic aldehyde) comprises a planar structure needed for possible DNA intercalation between base pairs. In our efforts to synthesize diandraflavone, the protected glucose and 2-deoxy galactose moieties have been synthesized. A glucose derived sugar residue has been attached to a phenyl acetylene moiety via β-C-glycosidic linkage. A second sugar, derived from galactose, has been xiv modified to match the natural product. The chromophore has also been prepared in a model system to ensure that future coupling and cyclization between the β-C aryl glycoside piece and the chromophore can occur. xv Chapter 1: Chemical and Biological Significance of C-Aryl Glycosides and Flavones 1.1 Introduction Nature

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