University of Missouri, St. Louis IRL @ UMSL Dissertations UMSL Graduate Works 6-15-2011 Development of New Strategies for Expeditious Oligosaccharide Synthesis Sophon Kaeothip University of Missouri-St. Louis, [email protected] Follow this and additional works at: https://irl.umsl.edu/dissertation Part of the Chemistry Commons Recommended Citation Kaeothip, Sophon, "Development of New Strategies for Expeditious Oligosaccharide Synthesis" (2011). Dissertations. 432. https://irl.umsl.edu/dissertation/432 This Dissertation is brought to you for free and open access by the UMSL Graduate Works at IRL @ UMSL. It has been accepted for inclusion in Dissertations by an authorized administrator of IRL @ UMSL. For more information, please contact [email protected]. Development of New Strategies for Expeditious Oligosaccharide Synthesis by Sophon Kaeothip A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) University of Missouri - St. Louis December 2010 Dissertation Committee Prof. Alexei V. Demchenko, Ph. D. (Chairperson) Prof. James S. Chickos, Ph. D. Prof. Michael R. Nichols, Ph. D. Prof. Rudolph E. K. Winter, Ph. D. Abstract Development of New Strategies for Expeditious Oligosaccharide Synthesis Sophon Kaeothip Doctor of Philosophy University of Missouri - St. Louis Prof. Alexei V. Demchenko, Chairperson The important role that carbohydrates play in biology and medicine has been the major incentive for devising new methods for chemical and enzymatic glycosylation. The chemical approach to oligosaccharides involves multiple synthetic steps and the development of new strategies that allow for streamlining the synthesis of these complex biomolecules is a significant area of research. The aim of this doctoral dissertation is to develop new reagents and efficient methodologies for oligosaccharide synthesis. It was found that siver(I) tetrafluoroborate can be used as a powerful activator of various glycosyl donors for oligosaccharide synthesis. This study evolved into the development of a very effective orthogonal strategy which allowed for the synthesis of a variety of oligosaccharide sequences with moderate stereoselectivity. Further studies showed that the improvement of stereoselectivity of glycosylation can be achieved in two different modes. First, we found that electron withdrawing protecting groups on the glycosyl acceptor can help to obtain excellent α-stereoselectivity. Second, the stereoselectivity of glycosidation of thioglycosides in the presence of bromine depends greatly on the anomeric orientation of II the leaving group. The mechanistic studies of this phenomenon were conducted using high field NMR and the developed methodology was applied to the synthesis of a range of therapeutically attractive carbohydrate-amino acid conjugates. III This dissertation is dedicated to my parents with love and respect IV Acknowledgements I owe my sincere gratitude and appreciation to my advisor, Prof. Alexei Demchenko, for accepting me as a PhD student, for his inspiring guidance, and for his patience during my PhD dissertation at University of Missouri-Saint Louis. I wish to thank my graduate committee members; Prof. James S. Chickos, Prof. Rudolph E. K. Winter, and Prof. Michael R. Nichols for their valuable suggestions and comments. I am very grateful to Dr. Papapida Pornsuriyasak who was a post-doctoral fellow in our laboratory for her kindly training when I started working in this group. I also would like to thank Prof. Rudolph E. K. Winter and Mr. Joe Kramer for their help with the mass spectrometry, Prof. Rensheng Luo for NMR spectrometry, and Prof. Nigam P. Rath for X-ray crystallography. I also would like to acknowledge Prof. Michael R. Nichols and his co-workers for their help with the biological activity testing. I would also like to express my special thanks to my colleagues, previous and current Demchenko group members, for their supports and discussions. I would like to thank the faculty and staff of the department of chemistry and biochemistry of UMSL for their support and providing me with pleasant working atmosphere. I wish to express extremely grateful to my parents and members in my family for their love, understanding, support and looking forward to my graduation. Finally, I would like to thank the American Heart Association, the National Science Foundation, Department of Chemistry and Biochemistry UM-St. Louis and the UM-St. Louis Graduate School Dissertation Fellowship for financial support during my doctoral studies. V Table of Contents List of abbreviations .....................................................................................................X Tables....................................................................................................................... XIV Figures...................................................................................................................... XVI Schemes .................................................................................................................. XVII Chapter I. Introduction 1.1 Introduction. Complex carbohydrates, chemical glycosylation, and conventional oligosaccharide synthesis......................................................................................2 1.2 Expeditious oligosaccharide synthesis: selective and chemoselective concepts.................................................................................................................5 1.3 Selective activation...............................................................................................8 1.3.1 Glycosyl bromides and chlorides..............................................................8 1.3.2 Glycosyl fluorides...................................................................................13 1.3.3 O-Linked glycosyl donors.......................................................................15 1.3.4 S-linked glycosyl donors.........................................................................27 1.3.5 Miscellaneous glycosyl donors (orthoesters, Se-glycosides, glycal/epoxides) ......................................................................................34 1.4 Multistep sequences based on selective activations............................................38 1.5 Semi-orthogonal approach..................................................................................43 1.6 Orthogonal activation..........................................................................................46 1.6.1 Fluorides and thioglycosides...................................................................47 VI 1.6.2 Thioglycoside and thioimidate................................................................48 1.6.3 Thioimidate-only (SBox and STaz glycosides) ......................................49 1.6.4 n-Pentenyl and propargyl activation .......................................................50 1.7 Selective and orthogonal activations in modern high throughput technologies......................................................................................52 1.7.1 Intramolecular glycosylations.................................................................52 1.7.2 One-pot synthesis....................................................................................53 1.7.3 Polymer-supported synthesis..................................................................60 1.8 Conclusions and future directions......................................................................64 1.9 References...........................................................................................................65 Chapter II. Evaluation of the applicability of Siver (I) tetrafluoroborate as a promoter for chemical glycosylation 2.1 Introduction.........................................................................................................80 2.2 Results and discussion........................................................................................81 2.3 Conclusions.........................................................................................................90 2.4 Experimental.......................................................................................................90 2.5 References.........................................................................................................101 Chapter III. Unexpected orthogonalilty of S-benzoxazolyl and S-thiazolinyl glycosides: Application to expeditious oligosaccharide assembly 3.1 Introduction.......................................................................................................106 3.2 Results and discussion......................................................................................107 VII 3.3 Conclusions.......................................................................................................117 3.4 Experimental.....................................................................................................118 3.5 References.........................................................................................................134 Chapter IV. On the stereoselectivity of glycosidation of thiocyanates, thioimidates and thioglycosides 4.1 Introduction.......................................................................................................138 4.2 Results and discussion......................................................................................140 4.3 Conclusions.......................................................................................................146