Abstract
Heparan sulfate (HS) and its structurally related heparin belong to the family of glycosaminoglycans. HS is ubiquitously distributed on the cell surface and in the basement membrane as well as the extracellular matrix, whereas H is found only in mast cells and some hematopoietic cells and is widely used as an anticoagulant drug. Biosynthesis of H/HS involves the formation of an initial glycosaminoglycan chain, comprising of alternating N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcA) jointed by 1,4-linkages. The subunit of D-glucuronic acid can be transformed into L-iduronic acid by C5-epimerase, the structure may be modified through a series of enzymatic reactions resulting in the various N- or O-sulfate patterns. H/HS play important roles in the physiologic and pathophysiologic processes, such as cell growth, blood coagulation, cell-cell interaction, metabolism, inflammatory processes, and virus infection.Recent studies have revealed the interactions between H/HS with various proteins. For example, the binding of fibroblast growth factor with fibroblast growth factor receptor can be activated by a few chemically synthesized H/HS-related di- and trisaccharides. However, these saccharides are not enough to characterize the detailed molecular properties of their binding complexes since there are 192 possible H/HS trisaccharides. will be fully synthesized through a novel orthogonal protection/deprotection strategy developed by our laboratory.In this thesis, we plan to use a common trisaccharide building block in combination of a novel orthogonal protection/deprotection strategy to prepare 48 trisaccharides. The other colleagues will use similar concept to synthesize the rest 144 units. The preparation of the D-glucopyranosyl derivatives 34 and 35 from compound 32 can be carried out via one-pot protection strategy in 6 and 4 steps, respectively. The trichloroacetimidate donor 30 can be derived from 33 in 7 steps. Coupling of 30 with 34 afforded the desired disaccharide 50 (71%) as a single a-isomer, which was subjected to assemble with 35 and a linker to yield the linker-attached trisaccharide 56 (69%) in a one-pot manner. We believe that 48 trisaccharides 73 can be efficiently obtained from 56 through a series of orthogonal deprotection, sulfonation, and oxidation.