Abstract
Heparan sulfate, which is a ubiquitous glycosaminoglycan on the cell surface, is comprised of alternating 1→4-linked D-glucosamine and uronic acid backbone. The highly heterogenous linear chain is decorated with a complex pattern of sulfation that has been associated with many important physiological mechanisms. Because of the difficulty in acquiring heparan sulfate carrying defined structures from nature, chemical synthesis acted as the main source of these important compounds for biological evaluation. Chemical syntheses allow the potential preparation of heparin sulfate oligosaccharides of different lengths and sulfation patterns with good purity. This dissertation describes an attractive method for the synthesis of eight heparan sulfate octasaccharides and provides an opportunity to prepare more octasaccharides of different structures. Herein, eight fully protected and linker-attached octasaccharide skeletons bearing different sets of residues were assembled in a modular and combinatorial manner. A representative octasaccharide was then subjected to divergent transformations to afford eight final compounds having the heparin sulfate structure and functionalizations. In Chapter 1, the cell-surface glycoconjugates and the biological functions of heparan sulfate are introduced. The recent advances in the synthesis of heparan sulfate oligosaccharides are reviewed in Chapter 2. Chapter 3 explains the retrosynthetic plan in attaining the octasaccharides. In Chapter 4, the preparation of monosaccharide building blocks and a new one-pot strategy in acquiring them are described. The synthesis of the disaccharide, tetrasaccharide and octasaccharide skeletons are laid out in Chapter 5 and the transformations toward the eight final heparin sulfate-based octasaccharides are specified in Chapter 6. Chapter 7 states the conclusions for the present synthetic work. Finally, the detailed experimental procedures and physical data of the compounds synthesized herein are provided in Chapter 8.