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STEREOSELECTIVE GLYCOSYLATIONS and SYNTHESIS of HYALURONAN BIOSYNTHESIS INHIBITORS by Gilbert Ochieng Wasonga a THESIS Submitted

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STEREOSELECTIVE GLYCOSYLATIONS and SYNTHESIS of HYALURONAN BIOSYNTHESIS INHIBITORS by Gilbert Ochieng Wasonga a THESIS Submitted STEREOSELECTIVE GLYCOSYLATIONS AND SYNTHESIS OF HYALURONAN BIOSYNTHESIS INHIBITORS By Gilbert Ochieng Wasonga A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE CHEMISTRY 2010 1 ABSTRACT STEREOSELECTIVE GLYCOSYLATIONS AND SYNTHESIS OF HYALURONAN SYNTHESIS INHIBITORS By Gilbert Ochieng Wasonga Stereochemical control is an important issue in carbohydrate synthesis. Glycosyl donors with participating acyl protective groups on 2-O have been shown to give 1,2-trans glycosides reliably under the pre-activation based reaction condition. In this work, the effects of additives and reaction solvent on stereoselectivity was examined using donors without participating protective groups on 2-O. We have established that the stereoselectivity could be directed by reaction solvent. The trend of stereochemical dependence on reaction solvent was applicable to a variety of reactions including the selective formation of β-mannosides. In the second part, 3-MeO-GlcNAc is efficiently prepared using a furanose oxazoline intermediate which is well suited for large scale synthesis without the need for extensive column chromatography. In addition, we have developed a robust and rapid procedure for the synthesis of 3-F-GlcNAc derivative required for inhibition studies of hyaluronan biosynthesis. In the course of our synthesis, we have shown the expanded utility of Lattrell-Dax method for carbohydrate epimerization reactions. II ACKNOWLEDGMENTS I would like to thank my advisor Professor Xuefei Huang for his guidance and support that have been instrumental in my graduate studies. Along the way, I have had the opportunity to be mentored by Doctor Youlin Zeng who was a very helpful mentor at the beginning of my chemistry research experience and I will always be grateful to him. Dr. Daniel Holmes was very helpful with 2D-NMR spectroscopy training which have been vital for my research. In addition, Dr. Daniel Jones and Lijun Chen have been very helpful in training and running mass spectroscopy. My experience and friendships developed with my past and present lab mates is something to cherish for a lifetime. From our interactions, I now have a better appreciation of people from different cultures which in many ways are similar to my own. I also want to thank my guidance committee members Dr. Babak Borhan, Dr. Gary Blanchard and Dr. William Wulff for their patience and serving on my committee. Finally, I would like to thank my family for I will not be this far without your love and support. iii 1 TABLE OF CONTENTS LIST OF TABLES .................................................................................................. v LIST OF FIGURES ................................................................................................ vi LIST OF SCHEMES............................................................................................... xi LIST OF ABBREVIATIONS AND SYMBOLS ................................................... xii CHAPTER 1 PRE-ACTIVATION BASED STEREOSELECTIVE GLYCOSYLATION 1.1 Introduction .................................................................................................. 1 1.2 Result and Discussions ................................................................................. 14 1.3 Conclusion .................................................................................................... 24 1.4 Experimental Section ................................................................................... 25 Appendix 1: Spectral data .................................................................................. 46 References .......................................................................................................... 96 CHAPTER 2 STEREOSELECTIVE GLYCOSYLATION OF AZIDO GLUCOSIDE 2.1 Introduction .................................................................................................. 107 2.2 Result and Discussion .................................................................................. 109 2.3 Experimental Section ................................................................................... 115 Appendix 2: Spectral data .................................................................................. 125 References .......................................................................................................... 137 CHAPTER 3 SYNTHESIS OF HYALURONAN SYNTHESIS INHIBITORS 3.1 Introduction .................................................................................................. 140 3.2 Result and Discussion .................................................................................. 144 3.3 Conclusion .................................................................................................... 151 3.4 Experimental Section ................................................................................... 152 Appendix 3: Spectral data .................................................................................. 165 References .......................................................................................................... 184 iv List of Tables Table 1.1 Effects of triflate salt additives on stereoselectivity ............... 20 Table1.2 Solvent effects on stereoselectivity .......................................... 21 Table 2.1 Glycosylations of donor 6 ....................................................... 111 Table 2.2 Glycosylations of donor 14 ..................................................... 113 v List of Figures Figure 1.1 1H-NMR compound 3 .......................................................................... 48 Figure 1.2 1H-NMR compound 4 .......................................................................... 49 Figure 1.3 1H-NMR compound 5 .......................................................................... 50 Figure 1.4 1H-NMR compound 6 .......................................................................... 51 Figure 1.5 1H-NMR compound ............................................................................. 52 Figure 1.6 1H-NMR compound 8 .......................................................................... 53 Figure 1.7 1H-NMR compound 9 .......................................................................... 54 Figure 1.8 1H-NMR compound 10 ........................................................................ 55 Figure 1.9 1H-NMR compound 13 ........................................................................ 56 Figure 1.10 1H-NMR compound 15 ...................................................................... 57 Figure 1.11 13 C-NMR compound 15 ..................................................................... 58 Figure 1.12 1H-NMR compound 15 ...................................................................... 59 Figure 1.13 13 C-NMR compound 16 ..................................................................... 60 Figure 1.14 gCOSY compound 16 ......................................................................... 61 vi Figure 1.15 gHMQC-coupled compound 16 ......................................................... 62 Figure 1.16 gHMQC-coupled (anomeric region expansion) compound 16 .......... 63 Figure 1.17 gHMQC-decoupled compound 16...................................................... 64 Figure 1.18 gHMBC compound 16........................................................................ 65 Figure 1.19 1H-NMR compound 17 ...................................................................... 66 Figure 1.20 13 C-NMR compound 17 ..................................................................... 67 Figure 1.21 gCOSY compound 17 ......................................................................... 68 Figure 1.22 gHMQC-coupled compound 17 ......................................................... 69 Figure 1.23 gHMQC-coupled (anomeric region expansion) compound 17 .......... 70 Figure 1.24 gHMQC-decoupled compound 17...................................................... 71 Figure 1.25 gHMBC compound 17........................................................................ 72 Figure 1.26 1H-NMR compound 18 ...................................................................... 73 Figure 1.27 13 C-NMR compound 18 ..................................................................... 74 Figure 1.28 gCOSY compound 18 ......................................................................... 75 Figure 1.29 gHMQC-coupled compound 18 ......................................................... 76 Figure 1.30 gHMQC-coupled (anomeric region expansion) compound 18 .......... 77 Figure 1.31 gHMQC-decoupled compound 18...................................................... 78 vii Figure 1.32 gHMBC compound 18........................................................................ 79 Figure 1.33 1H-NMR compound 20 ...................................................................... 80 Figure 1.34 1H-NMR compound 21 ...................................................................... 81 Figure 1.35 13 C-NMR compound 21 ..................................................................... 82 Figure 1.36 gHMQC-coupled compound 21 ......................................................... 83 Figure 1.37 gHMQC-coupled (anomeric region expansion) compound 21 .......... 84 Figure 1.38 gHMQC-decoupled compound 21...................................................... 85 Figure 1.39 gHMBC compound 21........................................................................ 86 Figure 1.40 1H-NMR compound 22 .....................................................................
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