Exploring new methods to control the stereoselectivity of glycosylation reactions

The synthesis of complex carbohydrate remains a challenge for synthetic chemists, especially in terms of stereocontrol (anomeric ratio) of glycosylation reactions. The stereoselective formation of glycosidic bonds depends indeed on numerous factors such as the reaction temperature, the solvent, the reagents concentration, the promoter and the coupling partners. In addition, the monosaccharide residues required for the assembly of larger saccharide structures are precious synthetic intermediates themselves as they require multistep synthesis. Large amount of starting material are usually consumed for the identification of the best reaction conditions using traditional batch procedures, and their optimization and subsequent scale-up of the optimized reaction conditions pose an additional hurdle. Continous-flow microfluidic devices offer a well-engineered approach to meet some of these challenges, especially in terms of better control of reaction parameters. Quite surprisingly, glycosylation reactions have been still little explored under continous-flow conditions, and only few example of this chemistry are reported in the literature.1 The aim of the present research project is to investigate the use of microfluidic reactor in carbohydrate chemistry area, with particular emphasis on the glycosylation reactions (especially in terms of stereoselection control). Initially, a panel of different glycosyl acceptors (primary and secondary) and different glycosyl donors (with or without neighbouring participating group at C-2 and with different leaving group at the anomeric carbon) were synthesized and employed in glycosylation reactions under batch conditions. Then, some glycosylation reactions were carried out under microfluidic conditions in order to compare their relative efficiencies. Stereochemical control of glycosylation reaction can be also achieved by using chiral promoter. Inspired by Fairbanks and co-workers who recently described glycosylation reactions promoted by a chiral Brønsted acid catalyst,2 we decided to explore the use of a chiral Lewis acid catalyst to induce stereoselective glycosylations. In particular, the stereochemical course of a model glycosylation reaction has been investigated using the trimethylsilyl esters derived from (R/S)-BINOL phosphoric acid.