Synthesis of Ketose-containing Microbial Glycans

Abstract

Molecules that include ketose residues are referred to as ketose-containing glycans. They have been identified in both prokaryotic and eukaryotic organisms where they serve important biological roles. To understand better the biological roles of ketose-containing glycans, chemical synthesis provides a useful tool to access probe molecules. However, there are many challenges that need to be addressed in the synthesis of molecules of this type. This thesis is focused on developing synthetic approaches to glycans with three different ketose residues. In Chapter 2, the synthesis of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) and its derivatives are described. In 2013, Whitfield and coworkers identified that the core of capsular polysaccharides (CPS) from Escherichia coli K1 and K5, and Neisseria meningitides group B, contain alternating -(24)- and -(27)--Kdo linkages. However, the biosynthesis of this CPS had not been definitively resolved when I started my thesis research. In this study, one -Kdo monosaccharide and two disaccharides with either a -(24)- or a -(27)-linkage were synthesized as the probe molecules for biosynthetic studies and high-throughput screens. Xylulose (Xul) is the second ketose that was studied in this thesis. -Xylulofuranose (-Xulf) moieties have been identified as components of microbial glycans. However, there have been no reports on synthesizing molecules with this ketose, particularly those containing -Xulf residues. I developed two methods for stereoselective xylulofuranosylation. In Chapter 3, moderate to good selectivity in xylulofuranosylation was observed with a variety of acceptors using conformationally-restricted donors. In Chapter 4, exclusive selectivity was obtained using a siloxane-protected donor that hindered the -face of the furanose ring. Both methods were applied to the synthesis of -D-Xulf-containing glycans that are present in microbial glycans. In Chapter 5, the third ketose, Fructose (Fru), was investigated. Fru is found in nature primarily in the -furanose form. Previous studies to synthesize -Fruf glycosides (an example of cis-glycosides) have focused on two different strategies: intramolecular aglycone delivery and the use of sterically-hindered donors. The strategy of using conformationally-restricted donors has not been reported although it has been shown to be a powerful method to synthesize cis-glycosides of aldofuranoses. Three different conformationally-restricted Fruf donors were synthesized and their use in glycosylation reactions provided stereoselectivity totally contrary to my expectation. The unexpected results are discussed in the context of the influence of side chain (hydroxymethyl groups) on stereoselectivity and compared to other related systems (arabinofuranosylation and xylulofuranosylation).