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A Thesis Entitled Thio-Arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation Of A Thesis entitled Thio-arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation of Chemical Glycosylations by Xiaoning Li Submitted as partial fulfillment of the requirements for the Master of Science Degree in Chemistry ___________________________ Advisor: Dr. Xuefei Huang ___________________________ College of Graduate Studies The University of Toledo August 2007 An Abstract of Thio-arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation of Chemical Glycosylations by Xiaoning Li Submitted as partial fulfillment of the requirements for the Master of Science Degree in Chemistry The University of Toledo August 2007 Oligosaccharides are usually found as protein or lipid conjugates in cellular systems. They play crucial roles in many biological processes. Among many approaches, organic synthesis is a very important way to obtain the desired oligosaccharides for biological studies. To date, no general synthetic procedures are available for oligosaccharide synthesis. Laborious synthetic transformations are generally required in order to obtain the desired regio- and/or stereo-selective control in oligosaccharide synthesis, due to their diverse and complex structures and many chemical equivalent ii hydroxyl functional groups. To achieve a rapid synthetic routine with high yields, a key step - glycosylation in oligosaccharide synthesis needs to be well understood. Thus an insight into the mechanism of glycosylation will provide valuable information potentially leading to the development of generalized glycosylation method. In this work, kinetic properties of glycosylation were evaluated by model reactions between three different series of glycosyl donors and three different glycosyl acceptors. The glycosylation mechanism was analyzed in the context of a linear-free energy relationship. In order to do that, three series of glycosyl donors and one glycosyl acceptor were synthesized and the Relative Reactivity Values (RRVs) of these donors were then determined by HPLC competitive assay. Hammett plots were plotted using obtained RRVs. A linear correlation was found that allows an accurate prediction of glycosylation reactivities. The negative slopes of the Hammett plots (ρ-values) show that electron donating substituents increase the rate of the reactions and the magnitudes of slopes can be rationalized by neighboring group participation and electronic properties of the glycon protective groups. RRVmethanol values (using methanol as acceptor under standardized reaction conditions) have been employed as a quantitative measure to guide the design of building blocks with requisite anomeric reactivities for reactivity based chemoselective glycosylation. We extensively studied glycosylation reactivity by varying the reaction conditions such as by using different carbohydrate acceptors, glycosylation promoters, solvent or by quenching reaction at different time. Our results indicate that the reactivity differential was found to be dependent upon the identity of the acceptor with the less reactive carbohydrate acceptors resulting in lower reactivity differential. This result points out that the rate determining step of glycosylation reaction should involve iii the nucleophilic attack of the acceptor onto oxacarbenium ions or similar reactive intermediates as deduced from Hammett plots. The solvent could also play a role in varying the relative reactivity between two glycosyl donors. However, the RRVs were consistent under different promoter activation or by quenching at different reaction time. The electron density of sulphur atom on glycosyl donor and the bonding energy between glycosyl donor and promoter were found as qualitative indicators for RRVs. The knowledge gained from our results can provide valuable insights into further improvement of the powerful chemoselective armed-disarmed glycosylation methodology and understanding of chemical glycosylation in general. iv ACKOWNLEDGEMENTS First of all, I would like to thank Dr. Xuefei Huang, my research advisor for his instructions on my graduate study and encouragements to my research activities, as well as his understanding of my careless omissions sometimes. I would like to thank all my lab members: Adeline Miermone, Balasubramanian Srinivasan, Bin Sun, Bo Yang, Gilbert Wasonga, Kheireddine El-boubbou, Lijun Huang, Luyuan Zhou, Nardos Teumelsan, Xiaowei Lu, Youlin Zeng, Yuqing Jing, Zhen Wang. I have learnt a lot from discussions with them either on group meetings or at casual time. There are many other people I would like to thank: To my committee members, Dr. Xiche Hu and Dr. Steven Sucheck for their discussions and help. To Dr. Viranga Tillekeratne, Dr. Richard Hudson, Dr. James T. Slama for their inspiring discussions on Organic Journal Clubs. To Dr. Yong Wah Kim for his NMR training. To Charlene Hansen-Morlock and Pam Samples for their day-to-day help. To the University of Toledo Department of Chemistry for the financial support. Finally but not least significantly to my family: my parents and brothers; as well as to many friends of mine either in America or in China v TABLE OF CONTENTS Abstract................................................................................................................................ii Acknowledgements..............................................................................................................v Table of Contents................................................................................................................vi List of Figures...................................................................................................................viii List of Tables.......................................................................................................................x List of Schemes………………………………………………………………...................xi List of Abbreviations........................................................................................................xiii 1. Background ………………………………………………………...............................1 1.1 Oligosaccharide Synthesis………….....................................................................1 1.2 Glycosylation Method and Thioglycosides...........................................................1 1.3 Reactivity-based Chemoselective Glycosylation...................................................2 1.4 Reactivity Tuning of Thio-arylglycosides with Para-substituted Aglycons..........3 1.5 Using Varyingly Substituted Thio-arylglycosides System as a Tool for Mechanistic Investigation of Glycosylation..........................................................5 2. Results and Discussion .................................................................................................7 2.1 Preparation of Glycosyl Donors.............................................................................7 2.2 Determination of the Rate of Glycosylation by NMR.........................................11 2.3 Determination of Relative Reactivity Values (RRVs).................……................13 2.4 Results of the Relative Reactivity Studies...........................................................16 2.5 Prediction of RRVs…………………………………………………..................18 vi 2.5.1 Prediction of Donor RRVs by Hammett Equation and Correlation of 1 H-NMR Anomeric Proton Chemical Shifts with σp Values………………………………………......................................18 2.5.2 A Computational Approach to Prediction of RRVs……....................20 2.6 Effects of Acceptor and Other Conditions on RRVs………………...................27 2.6.1 Reaction Time and Quantity of Promoter Used…………...................27 2.6.2 Effect of Different Promoters on RRVs…………………...................28 2.6.3 Effect of Saccharide Acceptors on RRVs………………....................29 2.6.4 Solvent Effect on RRVs…………………………………...................32 2.7 An Approach to Mechanistic Investigation on Glycosylation with RRVs Using Linear Free Energy Relationship.........................................................................36 3. Conclusion …………………………………………………………............................39 Experimental Section ...……….……………………………………............................40 References ………………………………………………………………......................56 Appendix: Spectral Data…………………………………………….............................66 vii LIST OF FIGURES 1. Background Figure 1. Blood Group O Antigen...............................................................................1 2. Results and Discussion Figure 2. Changes of a) donor concentration, b) reaction rate vs time; and c) reaction rate vs donor fraction conversion as measured by 1H-NMR.......12 Figure 3. HPLC Competitive Assay..........................................................................14 Figure 4. HPLC chromatograms a) before and b) after competitive glycosylation between donors 3d and 3e..........................................................................15 Figure 5. Hammett plots of log(RRV) of the three donor series vs σp......................17 1 Figure 6. Linear correlation of σp value and H chemical shift of anomeric proton.........................................................................................................19 Figure 7. Correlation of log(RRV) of GlcN donor series vs calculated Mulliken charges.......................................................................................................22 Figure 8. Correlation of log(RRV) of GlcN donor series vs calculated bonding energies (simplified model).......................................................................24
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