Development of strategies for construction of thioglycoside building blocks corresponding to repeating triads of Cryptococcus neoformans GXM capsular polysaccharide

Abstract: This thesis focuses on the development of methods for synthesis of thioglycoside building blocks corresponding to the repeating units of the capsular polysaccharide (CPS) of Cryptococcus neoformans, an opportunistic fungal pathogen. The building blocks are suitable for construction of large synthetic oligosaccharides related to the native CPS-structures which are to be used in biological studies in order to identify protective epitopes with the aim to develop a glycoconjugate vaccine against C. neoformans infections.Chapter 3 describes the improved synthesis of di- and trisaccharide glucuronic acid-containing thioglycoside blocks by introduction of the carboxylic acid motif at the di- and trisaccharide level through oxidation of a glucose residue. The new approach requires a number of extra steps, but has proven to be more reliable and more easily reproducible since problems encountered in glycosylations with glucuronic acid donors and benzylation of glucuronic acid-containing derivatives are circumvented.In Chapter 4 the development of a synthetic route to xylose-substituted tri- and tetrasaccharide building blocks where the protecting group strategy allows for orthogonal glycosylations with thioglycoside acceptors is discussed.Chapter 5 describes the synthetic pathway to the glucuronic acid-containing derivatives according to the methodology developed in Chapter 4 and the assembly of a hexasaccharide building block corresponding to the repeating triad of serotype A.In Appendix ? an alternative strategy for synthesis of glucuronic acid-substituted derivatives by direct introduction of a perbenzylated glucuronic acid trichloroacetimidate donor where stereoselectivity is achieved through the use of an 1,6-anhydro acceptor.