NEW OPPORTUNITIES FOR CARBOHYDRATE CHEMISTRY AND GLYCOSYLATION – SWEETCAT

The steady expansion of glycoscience, the field exploring the structures and functions of carbohydrates, provides many opportunities and challenges for chemists in the ?eld of synthetic oligosaccharide and glycoconjugate research. Within carbohydrate chemistry there is arguably no reaction more important than the formation of glycosidic bonds — those between a sugar and a hydroxyl or other functional group of another molecule — known as glycosylation. The stereoselective construction of glycosidic linkages has long been, and continues to be, one if not the main challenge in synthetic carbohydrate chemistry. It generally involves a key intermediate, the putative glycosyl cation, considered for long as a theoretical species. Exploiting non-nucleophilic superacids (namely HF/SbF5) and their ability to stabilize cationic intermediates, we have recently been able to produce and study such cations for the first time in a condensed phase. Their conformations have been elucidated and preliminary results demonstrate that they can be engaged as glycosyl donors in coupling reactions with weak nucleophiles to produce clean glycoconjugates in a stereocontrolled manner.

Over the years, both the appearance of more sophisticated methods to assemble carbohydrates to oligosaccharides with increased complexity and the lack of a universal glycosylation methodology has pointed the necessity to better understand the effects and parameters that control the reactivity and selectivity of glycosylation to improve this key process. Its efficiency and stereoselectivity are affected by a multitude of factors that are commonly considered to exert their influence at the level of the glycosyl cation in terms of both reactivity and face selectivity.

With the glycosyl cation in hand, we are settled to examine these parameters and gain insights into the glycosylation reaction. Nevertheless, their study in batch would be extremely time and material consuming, greatly slowing the practice and pace of research and development of this reaction. Furthermore, we have identified some technical obstacles that have to be solved regarding both the generalization of the glycosyl ion generation and its use in glycosylation reaction. This includes safety considerations, control of reaction parameters, use of suitable carbohydrate precursors. As a consequence, flow chemistry constitutes an ideal tool for this project as microfluidic devices offer great technical opportunities (safe use of hazardous chemicals, short reaction times and small volumes and quantities involved, accumulation of reactive intermediates, ordering fluids in laminar flow, fine tuning of the reaction parameters). The study of glycosyl cations derived from modern glycosyl donors exploiting flow chemistry should have a significant impact on the fundamental understanding of the glycosylation reaction. Their trapping with weak nucleophiles should also initiate novel carbohydrate reactivity. This motivates our application to the DS10 challenge of ANR “Défi des autres savoirs”.

IN THIS PROJECT WE WILL COMBINE CARBOHYDRATE CHEMISTRY, SUPERACID METHODOLOGY AND FLOW CHEMISTRY TOOLS SUPPORTED BY NMR AND COMPUTATION:
A) TO STUDY THE GLYCOSYL CATIONS FURTHER AS WELL AS THE MAIN FACTORS THAT IMPACT THEIR STRUCTURE AND REACTIVITY
B) TO EXPLOIT THEM AS GLYCOSYL DONORS IN ORIGINAL SUPERACID-CATALYZED COUPLING REACTIONS WITH UNUSUAL NUCLEOPHILES TO DELIVER UNPRECEDENTED CARBOHYDRATE DERIVATIVES THAT COULD NOT BE REACHED BY CLASSICAL GLYCOSYLATION.