Synthesis and Applications of Epicatechin And
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SYNTHESIS AND APPLICATIONS OF EPICATECHIN AND EPIAFZELECHIN DERIVATIVES FROM PROANTHOCYANIDINS FU CAILI NATIONAL UNIVERSITY OF SINGAPORE 2010 SYNTHESIS AND APPLICATIONS OF EPICATECHIN AND EPIAFZELECHIN DERIVATIVES FROM PROANTHOCYANIDINS FU CAILI B. Eng. China Agricultural University M. Eng. China Agricultural University A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements The last four years have been one of the most important stages in my life. The experience in my Ph.D. period will benefit me for a lifetime. I would like to take this opportunity to express my immense gratitude to all those who have kindly helped me and all those who have made my graduate life at NUS both productive and enjoyable. At the very first, I am honored to express my deepest gratitude to my dedicated supervisor, Dr. HUANG Dejian. This thesis would not have been possible without his able supervision. He has offered me a great many of invaluable ideas and great suggestions, profound knowledge, and rich research experience. From him, I learn not only the knowledge, but also the professional ethics, both of which will stay with me for many years to come. His encouragement, patience and kindness throughout all these years are greatly appreciated and I am very much obliged to his efforts of helping me finishing the dissertation. My most sincere gratitude is expressed to the following people for their various contributions to this research effort: Ms. Quek Yi Ling, Ms. Chen Wei, Ms. Tan Kheng Ling, Ms. Xie Bingbing, Ms. Ng Wei Ling, Ms Wendy Wen Yi Leong, Ms Amylia Bte Abdul Ghani and Mr. Ni Runyan from the National University of Singapore (NUS) for their contribution in various experiments. Dr. Wang Shuhua, Dr Yao Wei, Dr. Feng Shengbao and Ms. Koh Lee Wah from NUS for their technique support. Mdm. Lee Chooi Lan, Ms. Lew Huey Lee, Ms. Jiang Xiaohui and Mr. Abdul Rahman bin Mohd Noor for their generous assistance in the laboratories. Mdm Wong Lai Kwai, Mdm Lai Hui Ngee, Mdm. Han Yan Hui and Miss Tan Geok Kheng from the Chemical, Molecular and Materials Analysis Centre (CMMAC), NUS for their i assistance in mass spectrometry, nuclear magnetic resonance spectroscopy, and Single crystal X-Ray diffraction analysis. Last, but certainly not the least, I would like to thank my family. I want to express my gratitude to my dearest wife, for her unceasing love and continuous support. I also want to thank my parents for their love and support all the way. From the bottom of my heart, I thank all my friends whose name may not be mentioned one by one here, but had never hesitate to lend me their helping hands whenever I am in need. Fu Caili August 2010 ii Table of Contents page Abstract...................................................................................................................viii List of Figures..............................................................................................................x List of Tables.............................................................................................................xiv List of Schemes...........................................................................................................xv List of Abbreviations.................................................................................................xvi Chapter 1 Literature Review 1.1. Structures, sources and bioavailability of proanthocyanidins............................1 1.1.1 Structure of proanthocyanidins....................................................................1 1.1.2. Analytical methods of proanthocyanidins..................................................5 1.1.3 Sources and contents of proanthocyanidins...............................................11 1.1.4 Absorption and bioavailability of proanthocyanidins................................12 1.2. Bioactivities of proanthocyanidins...................................................................14 1.2.1 Antioxidant activities................................................................................14 1.2.2 Antibacterial activities..............................................................................16 1.2.3 Prevention of cardiovascular diseases.......................................................19 1.2.4 Anticancer and antiinflammatory activities...............................................20 1.2.5 Other bioactivities......................................................................................21 1.3 Epicatechin derivatives from proanthocyanidins and their bioactivities.....22 1.4. Stereochemistry of epicatechin derivatives................................................24 1.5 The aim of this research.....................................................................................26 iii Chapter 2 Isolation, Purification and Characterization of Proanthocyanidins from Mangosteen Pericarps 2.1 Introduction.......................................................................................................28 2.2 Results and discussion.......................................................................................28 2.2.1 Isolation of proanthocyanidins from mangosteen pericarps......................28 2.2.2 Structural characterization.........................................................................30 2.2.3 Thiolysis....................................................................................................35 Chapter 3 Comparison among Different Proanthocyanidins 3.1 Introduction.......................................................................................................38 3.2 Results and discussion.......................................................................................38 3.2.1 Extraction and NMR analysis of cocoa proanthocyanidins.......................38 3.2.2 Synthesis of (2R,3R,4S)-2-(3,4-dihydroxyphenyl)-4-(2-hydroxy-4,6- dimethoxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol, 1...............................40 3.2.3 Optimization of the depolymerizing condition for carbon nucleophile, 3,5- dimethoxyphenol................................................................................................41 3.2.4 Depolymerization of MPPs by methyl thioglycolate.................................42 3.2.5 Comparison among proanthocyanidins from four sources........................44 Chapter 4 Synthesis of Epicatechin Derivatives from Mangosteen Pericarp Proanthocyanidins 4.1 Introduction.......................................................................................................48 4.2 Results and discussion.......................................................................................48 4.2.1 Regioselective protecting of catechins......................................................49 4.2.2 Synthesis of epicatechin derivatives from MPPs.......................................51 Chapter 5 Isolation, Identification and modification of Proanthocyanidins from Rhizomes of Selliguea feei iv 5.1 Introduction......................................................................................................63 5.2 Results and discussion.......................................................................................64 5.2.1 Isolation and characterization of proanthocyanidins from the rhizomes of Selliguea feei.......................................................................................................65 5.2.2 Synthesis of four epiafzelechin derivatives...............................................71 Chapter 6 Applications of Sulfurcontaining Epicatechin Derivatives for Proanthocyanidins Synthesis 6.1 Introduction.......................................................................................................76 6.2 Results and discussion.......................................................................................77 6.2.1 Kinetics of the dethiolation of three sulfur-containing epicatechin derivatives...........................................................................................................77 6.2.2 Synthesis of procyanidin B2 via base-catalyzed condensation.................79 6.2.3 Synthesis of epicatechin alkaloids.............................................................81 Chapter 7 Conclusions and Suggestions for Future Work 7.1 Conclusions.......................................................................................................85 7.2 Suggestions for future work..............................................................................87 Chapter 8 Experimental procedures 8.1 Instrument and reagents...................................................................................88 8.2 Characterization of mangosteen pericarp proanthocyanidins............................90 8.2.1 Isolation and identification of mangosteen pericarp proanthocyanidins...90 8.2.2 Thiolysis of mangosteen pericarp proanthocyanidins...............................91 8.3 Comparison among different proanthocyanidins.............................................91 8.3.1 Extraction and characterization of cocoa proanthocyanidins....................91 8.3.2 Depolymerization of MPPs with 3,5-dimethoxyphenol............................92 v 8.3.3 Synthesis of 2-((2R,3S,4S)-2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxychroman-4-ylthio)acetate 2 from MPPs.............................................92 8.3.4 Gram-scale synthesis of 2 from mangosteen pericarps directly..............94 8.4 Screening regioselective protecting reagents of catechin derivatives...............94