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Synthesis of a Resveratrol Glycinate Derivative. Shelley Marie Van Cleve East Tennessee State University

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Synthesis of a Resveratrol Glycinate Derivative. Shelley Marie Van Cleve East Tennessee State University East Tennessee State University Digital Commons @ East Tennessee State University Electronic Theses and Dissertations Student Works 5-2011 Synthesis of a Resveratrol Glycinate Derivative. Shelley Marie Van Cleve East Tennessee State University Follow this and additional works at: https://dc.etsu.edu/etd Part of the Medicinal-Pharmaceutical Chemistry Commons Recommended Citation Van Cleve, Shelley Marie, "Synthesis of a Resveratrol Glycinate Derivative." (2011). Electronic Theses and Dissertations. Paper 1312. https://dc.etsu.edu/etd/1312 This Thesis - Open Access is brought to you for free and open access by the Student Works at Digital Commons @ East Tennessee State University. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Digital Commons @ East Tennessee State University. For more information, please contact [email protected]. Synthesis of a Resveratrol Glycinate Derivative A thesis presented to the faculty of the Department of Chemistry East Tennessee State University In partial fulfillment of the requirements for the degree Master of Science in Chemistry by Shelley Marie Van Cleve May 2011 Dr. Yu Lin Jiang, Ph. D Chair Dr. Kady, Ph. D Dr. Vasiliev, Ph. D Keywords: Polyphenols, Stilbenoid, Resveratrol ABSTRACT Synthesis of a Resveratrol Glycinate Derivative by Shelley Marie Van Cleve Recently, the compound resveratrol has had media attention as an anti carcinogen. However, the bioavailability of resveratrol is low in the human system due to its hydrophobic nature. Therefore, it must be administered in high dosages to be effective. A plethora of derivatives have been synthesized that have the potential of resveratrol but sadly share low bioavailability. The first effort of this research was an attempt to produce a more hydrophilic ester of resveratrol. Failing this, the final product was synthesized using a glycine derivative to produce 4-[(1E)-2- (3,5-diacetyloxyphenyl)ethenyl]phenyl N-[(1,1-dimethylethoxy)carbonyl]-glycinate. 2 DEDICATION In loving memory of my grandfather, John Edward “Buck” Van Cleve Jr. 3 ACKNOWLEDGEMENTS I thank Dr. Yu Lin Jiang for allowing me to participate in his research efforts and for his patience throughout this project. I thank Dr. Kady and Dr. Vasiliev for their constructive feedback while serving on my thesis committee. I am grateful to the faculty of the chemistry department for the experience and knowledge given me. Words cannot express my gratitude to my family for their continuous support throughout my graduate studies. I am thankful for having such wonderful friends as Travis Heath, Sai Konda, and Averil Chaney throughout this experience. And lastly I thank Mrs. Rasnick who watched over all of us. 4 CONTENTS Page ABSTRACT………………………………………………………………………………………………2 DEDICATION…………………………………………………………………………………………....3 ACKNOWLEDGEMENTS……………………………………………………………………………....4 LIST OF TABLES………………………………………………………………………………………...9 LIST OF FIGURES……………………………………………………………………………………...10 LIST OF SCHEMES………………………………………………………………………………………11 Chapter 1. INTRODUCTION…………………………………………………………………………....12 Botanical Classification of Resveratrol………………………………………………..14 Phytoalexin………………………………………………………………...…14 Stilbene……………………………………………………………………….14 Chemical Classification of Resveratrol……….……………………………………….15 Functional Group Activity…………………..……………………………...15 Isomerism………………………………………………………..….............18 Resveratrol as a Pharmaceutical Drug………………………………………………….18 Dietary Supplement….…………………………………………………...…18 5 The French Paradox………..………………………………….……………...19 Various Medicinal Applications……………….…………………………....19 Drawbacks of Resveratrol…………………………………………………....20 Research Effort…………………………………………………………………………20 2. EXPERIMENTAL…………..………………………………………………………………....24 General Methods……………..…………………………………………………………..24 Synthesis of 2-(2-(2-Chloroethoxy)ethoxy)ethanoic acid 2...........................25 Synthesis of Methyl 2-(2-(2-Chloroethoxy)ethoxy) acetate 3…………...….26 Synthesis of Methyl 2-(2-(2-Iodoethoxy)ethoxy) acetate 4………………....26 Synthesis of 4’-(2-{2-[Carboxymethoxy)ethoxy]ethoxy})-3,5 hydroxystilbene 5…………………………………………………………...27 Synthesis of 3, 5, 4’-Tri-O-acetyl-resveratrol 6………………………….....28 Synthesis of 3, 5,-Di-O-acetyl-resveratrol 7…………………………..……29 Synthesis of 4’-(Ethyl 6-oxyhexaneoate) 3, 5,-Di-O-acetyl-resveratrol 8 ....30 Synthesis of 4-[(1E)-2-(3,5-Diacetyloxyphenyl)ethenyl]phenyl N-[(1,1- dimethylethoxy)carbonyl]-glycinate 9……………………………………...31 3. RESULTS AND DISCUSSION……………………………………………………………....32 Synthesis of 2-(2-(2-Chloroethoxy)ethoxy)ethanoic acid 2…………..…………………32 Synthesis of Methyl 2-(2-(2-Chloroethoxy)ethoxy) acetate 3…………...………………34 6 Synthesis of Methyl 2-(2-(2-Iodotheoxy)ethoxy) acetate 4...……………..…………....35 Synthesis of 4’-(2{2-[Carboxymethoxy)ethoxy]ethoxy})-3,5 Hydroxystilbene 5.................…………………………………………………………….36 Synthesis of 3, 5, 4’-Tri-O-acetyl-resveratrol 6…………...…….…………………...…..40 Synthesis of 3, 5,-Di-O-acetyl-resveratrol 7…........……………………………………..42 Synthesis of 3, 5-Di-O-acetyl (4’-ethyl 6-oxyhexanoate) stilbenes 8………..…………..43 Synthesis of 4-[(1E)-2-(3,5-Diacetyloxyphenyl)ethenyl]phenyl N-[(1,1- dimethylethoxy)carbonyl]-glycinate 9…………...………………………….…………...45 CONCLUSION………………………………………………………………………………...…47 REFERENCES…………………………………………………………………………………………….48 APPENDICES…..………………………………………………………………………………………...52 1 APPENDIX A. H NMR Spectrum of Compound 2 in CDCl3 ……….……………….52 1 APPENDIX B. H NMR Spectrum of Compound 3 in CDCl3 …………...………….…53 1 APPENDIX C. H NMR Spectrum of Compound 4 in CDCl3………………………....54 1 APPENDIX D. H NMR Spectrum of Compound 5 in MeOD ………………………..55 1 APPENDIX E. H NMR Spectrum of Compound 6 in MeOD………….…………….56 1 APPENDIX F. H NMR Spectrum of Compound 7 CDCl3…………….……………..57 1 APPENDIX G. H NMR Spectrum of Compound 8 in CDCl3…………………………58 1 APPENDIX H. H NMR Spectrum of Compound 9 in CDCl3…………………………59 7 13 APPENDIX I. C NMR Spectrum of Compound 9 in CDCl3…………………………60 APPENDIX J. IR Spectrum of Compound 9………………………………..………….61 APPENDIX K. GCMS Spectrum of Compound 9…………..……………...………….62 VITA…………………………………………………………………………………………………...….63 8 LIST OF TABLES Table Page 1. List of foodstuffs containing resveratrol…………...…………...……………………………………...13 2. Variable bases for Williamson etherification reaction………………...….…………………………....39 3. Experimental temperatures for the Williamson etherification reaction………….……….…………...39 4. The addition of reagents in various experiments for the Williamson etherification………….……....40 9 LIST OF FIGURES Figure Page 1. The synthetic route of resveratrol in plants ………………………….………………..……………...15 2. The resonance structures for abstraction at the 4’ position…………………………………………...16 3. The resonance structures for abstraction at the 3, 5 positions……………………………...................17 4. The molecular structures of cis and trans-resveratrol………………….……………………………...18 5. The structures of the di and tri substituted resveratrol product...…………………………………..…38 10 LIST OF SCHEMES Scheme Page 1. Proposed Synthetic Pathway for Method 1.………………………………………………..................21 2. Proposed Synthetic Pathway for Method 2…………………………………………………………...22 3. Proposed Synthetic Pathway for Method 3…………………………………………….……………..23 4. Scheme for the Jones Oxidation…….....……………………………………………………..……33-34 5. Scheme for the Fischer Esterification…...………………...………………………………………..…35 6. Scheme for the Finkelstien Reaction…………………………...……………………………………..36 7. Scheme for the Williamson Etherification 1st Method.........………………………………………....37 8. Scheme for the Possible Epoxide Formation…...…………………………………………..................37 9. Scheme for the Acetylation of the Phenol Groups…...…………………………………………….....41 10. Scheme for the Enzymatic Hydroxylation…………...……………………………………………....43 11. Scheme for the Williamson Etherification 2nd Method…………...……………………………….….44 12. Scheme for the Final Analogue of Resveratrol…...…………………………………………………..46 11 CHAPTER 1 INTRODUCTION "Wine is the most healthful and most hygienic of beverages"[1]. Louis Pasteur (1822-1895) Fast forward 100 years to 1939, resveratrol was first discovered by M. Takaoka in the roots of the white hellebore. Eventually the compound was found in roughly 70 different plant species, paramount among them is the grape [2]. Resveratrol is the compound responsible for the advantageous characteristic of wine [3]. By the 1990s resveratrol had been studied by many research groups for its vast potential in several medicinal treatments and pharmaceutics. Due to its substantive antioxidant characteristic, it has been targeted as the key compound responsible for the French Paradox, the surprisingly epicurean yet non-detrimental lifestyle [4]. The compound has been found in several different plant genres (Table 1). 12 Table 1. A list of various foodstuffs containing resveratrol [5] Foodstuffs Reference Grape Jeandet et al. 1995a, Wang et al. 2005, Liew et al. 2005, Gonzalez-Barrio et al. 2005, Yilmaz et al. 2004, Roldan et al. 2003 Wine Cantos et al. 2003, Wang et al. 2002, Vian et al. 2005. Shu et al., 2005 Gambuti et al., 2004 Bilberry Ehala et al. 2005, Lyons et al. 2003, Rimando et al. 2004 High-Bush, Low Bush, Rabbit Lyons et al. 2003., Rimando et al. 2004 eye, Elliot’s Blueberry Cranberry Ehala et al. 2005, Wang et al. 2002, Rimando et al. 2004 Deerberry Rimando et al. 2004 Ligonberry Rimando et al. 2004 Sparkleberry Rimando et al. 2004 Partridgeberry Rimando et al. 2004 Strawberry Ehala et al. 2005 Red Currant Ehala et al. 2005 Rhubarb Kageura et al. 2001 Pistachio Tokusoglu et al 2005 Peanut Liu et al. 2003, Tokusoglu
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