New strategies for the total synthesis of microbial glycans

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The microbial world represents an inexhaustible source of sugar-derived molecules, showing astonishing structural diversity, biological functions, and therapeutic properties. As sugar-derived metabolites are found in the form of complex mixtures, chemical synthesis of microbial glycans stands as a tantalizing opportunity to gain insight into their biological and therapeutic properties. Along these lines, the main objective of our research program is to develop innovative synthetic approaches enabling the preparation of therapeutically relevant microbial glycans. For the next five-year period, we propose to work on four different research themes, which have been designed to make significant progress toward our long-term goal. In a first theme, we propose to synthesize the repeating unit (RU) of cepacian, a polysaccharide (PS) expressed at the surface of Burkholderia cepacia complex, a group of opportunistic pathogens causing severe nosocomial infections. The RU of cepacian is an oligomer composed of seven sugar residues, some of them bearing ester substituents at specific positions. The presence of a highly branched glucuronic acid residue in a specific "alpha" configuration represents an important synthetic challenge, which we will try to solve capitalizing on intramolecular reactions. In a second theme, we will synthesize compounds that can mimic Kdo, an eight-carbon carboxylic acid-containing bacterial sugar, which stands as a crucial building block for the elaboration of membrane-linked PSs produced by pathogenic Gram-negative bacteria. We will replace the intracyclic oxygen atom of Kdo with a nitrogen to generate an unprecedented library of compounds called "Kdo iminosugars". These sugar mimics could be used to inhibit - or probe - the biosynthesis of bacterial PSs. In a third theme, we will investigate the biosurfactant content of Pantoea ananatis, a non-pathogenic bacterium, which produces glucolipid featuring macrocycles that we have called "ananatosides". We will develop expeditious chemo-enzymatic approaches for the synthesis of ananatoside-like biosurfactants and their more water soluble or dimeric derivatives. In a last research theme, we will investigate how rare bacterial sugars called "idopyranosides" can react to form stable and isolable "glycosidic conformers", which are the same compound presenting two different conformations. Thorough mechanistic insights will be gathered from experimental data and calculations. This knowledge will be applied to the synthesis of the RU of a PS produced by Campylobacter jejuni, a bacterium that is the main trigger of the Guillain-Barré auto-immune syndrome. Several aspects of our research program will lead to fundamental advances in synthetic chemistry. Importantly, the sugar-based compounds that will be prepared over the course of this research program could generate benefits for the health of Canadians as novel therapeutics, prophylactics, and biomaterials.