Total Synthesis Of Naturally Occurring Or Biologically Important Sulfated Oligosaccharides Using Orthogonal Protections

Carbohydrates are the most abundant biopolymers in nature, and play diverse roles in biological systems. Cell surface glycans have been implicated in numerous biological processes, such as cellular recognition and information transfer. Thus, oligosaccharides are increasingly employed to solve important problems in glycobiology and drug discovery. However, a major impediment to glycobiology and glycomedicine is the lack of adequate, pure and structurally defined oligosaccharides. In many cases, the procurement of well-defined oligosaccharides typically relies on chemical synthesis.However, there are no general approaches for the chemical synthesis of complex carbohydrates of biological importance. As a result, oligosaccharide synthesis requires custom-tailored strategies for each target, and may take months or even years to be completed. Two major challenges encountered in oligosaccharide synthesis are regioselective transformations of polyhydroxys and stereoselective construction of glycosidic linkages. Recently, synthetic glycochemists have developed increasingly versatile methods for oligosaccharides synthesis. However, oligosaccharide synthesis still remained technically challenging and time consuming. To date, synthesis of complex oligosaccharides can be achieved only in few laboratories with carbohydrate expertise.Sulfated glycans, including marine fucoidans and glycosaminoglycans, are a family of complex carbohydrates with structural diversities and various biological activities. Recently, sulfated oligosaccharides increasingly became synthetic targets due to biological importance and potential in drug discovery. In this dissertation, we focus on the total synthesis of naturally occurring or biologically important sulfated oligosaccharides. Synthetic strategies and methods, including orthogonal protections, were developed to address reactivitiy and selectivity problems, and led to successful total synthesis of target oligosaccharides in both efficient and stereoselective manner.In chapter 2, we report the first chemical synthesis of a highly sulfated tetrasaccharide, as the rare sequence in the galactofucan isolated from the brown alga Sargassum polycystum. The construction of the multiple contiguous 1,2-cis glycosidic linkages was achieved with exclusive stereoselectivities by judicious choice of synthetic strategy, building blocks and an understanding and application of solvent effects. The orthogonally protected galactose building block was proved to be a crucial and ideal donor to build up the 1,2-cis-α-galactosidic bond, and also could enable the convergent [2+2] assembly of tetrasaccharide backbone. In addition,1H and 13C signals of the synthesized oligosaccharides were fully assigned on the basis of 2D NMR techniques.In chapter 3, the first chemical synthesis of the extracellular phophomannan pentasaccharide of Pichia holstii NRRL Y-2448 was described. To build up the core sequence connected by α-(1-3)-mannosidic bonds, several synthetic strategies were investigated including preactivation-based iterative one-pot glycosylation and two-direction convergent assembly. Unfortuately, these strategy failed to work mainly due to unexpected low reactivities of α-(1-3)-linked oligomannan thioglycosides. According to Crich’s mannose/glucose phenomenon and our computational study, the O2-C2-C3-O3 torsional effect was considered to be the origin of super-disarming effect.To solve this problem, an alternative strategy of "linear iterative assembly starting from non-reducing end" was developed to construct the α-(1-3)-linked mannan and thus applied successfully in the total synthesis of target pentasaccharide. The internal and non-reducing end building blocks with orthogonal protections were successively coupled to the reducing end acceptor to provide a pentasaccharide precursor, which was then phosphorylated and deprotected to afford the target phosphomannan pentasaccharide. In addition, the sulfated derivative of this target mannan was synthesized through global sulfation transformation.On the basis of assembly strategy described in chapter 3, we developed an efficient modular strategy for the systematic synthesis of a series of sulfated mannan oligosaccharides in chapter 4. A semi-library of D-mannose building blocks with orthorgonal protections was synthesized via a set of systematic transformations. Then, reducing end, internal, and non-reducing end building blocks selected from this semi-library were successively coupled via a unitized linear assembly approach, providing orthorgonally protected oligosaccharides with various glycosidic linkages. The protecting groups in these precursors would be cleaved orthorgonally in different orders, and the resulting poly-alcohols were then subjected to sulfation. These orthogonal transformations would lead to a series of sulfated mannan oligosaccharides bearing different glycosidic linkages and sulfation patterns. In this respect, four sulfated mannan oligosaccharides and more precusors with different structural features were synthesized.