Abstract
Heparan sulfate (HS) is a member of the glycosaminoglycan (GAG) family and close in structure to heparin (HP). HS and HP are structurally related linear polyanionic polysaccharides characterized by a repeating disaccharide unit of uronic acid [either □-L-iduronic (IdoUA) or □-D-glucuronic acid (GlcUA)] attached to a □-D-glucosamine (GlcNH2) unit. Although HP and HS have similar structural skeletons, their biological roles in vivo are quite different. There was a rapid growing interest in the structure and function of heparin sulfate whose heterogeneity enable these molecules to play important roles in various processes in the body. This dissertation is written to provide readers with a detailed review of the chemistry, structure, biological functions, and our contribution to this significant issue through synthesis of a full HP/HS disaccharide building block library.Chapter 1 describes cell surface environment and the definition of GAG family in the beginning. Furthermore, structural characterization of HP/HS molecules and their biological properties lead us to a deeper understanding of the relationship between heparin and heparan sulfate.Chapter 2 summarizes ten pioneers’ works in the literature reports and reveals the synthetic urgency of these molecules. Chapter 3 describes our concerns with HP/HS studies, our specific aims to solve the problems as well as the retro-synthetic plan.Chapters 4 to 6 illustrate our preparation of monosaccharide building blocks. Chapter 4 outlines the synthesis of four D-glucosamine glycosyl donors, in seven to eight steps, starting from D-glucosamine hydrochloride. Chapter 5 provides the synthetic schemes leading to two glucosyl acceptors. “A regioselective one-pot protection of carbohydrates” was developed and applied. Chapter 6 describes the process to afford two idopyranosyl acceptors, a rare unit in nature, via L-ido epoxide as a key intermediate.Chapter 7 outlines the synthesis of 48 disaccharide building blocks, including 16 azido-containing disaccharide, 16 N-acetylated disaccharides and 16 N-Cbz disaccharides. Finally, chapter 8 describes the preparation of a series of ten parent disaccharides through two common intermediates, linker-attached □-D-glucuronic and □-L-iduronic acid triol, to exemplify the feasibility of our strategies for our synthesis.Chapter 9 concludes our synthetic work described in chapters 4 to 8, and chapter 10 provides the experimental details of all of our synthesis work for this dissertation.