Exploring Regioselective 5N-acylation of Neuraminic acid

Abstract: In this project, a regioselective method to deprotect and acylate the amide on C5 of sialic acid is explored. Sialic acid is one of the most complex monosaccharides and is an important ligand in many higher organisms in intercellular cell communication. The most prominent example is related to the immune system. Sialic acids are attached as the terminal carbohydrate on cell surface glycans, which is one of the unique patterns, used to distinguish between enemy and friend. Most pathogens need to take up sialic acid from their host, either to use it as an additional energy source or to incorporate it in their cell surface glycans to mimic the host cells. This mechanism leading to disguise is called molecular mimicry. The long-term aim is to find sialic acid derivatives to clog the transporters of the pathogens, resulting in a better immune response. Synthesising derivatives of sialic acid isn’t trivial due to its carboxylic acid function next to the anomeric hydroxyl group, four additional hydroxyl groups and an amide. This multitude of functional groups requires elaborate protection group strategies, which make it possible to address functional groups regioselectively. The simplest protecting strategy for sialic acid is the esterification of the carboxylic acid and per acetylation of all the hydroxyl groups. The problem was to remove just one of these acetyl groups. The new method, which is explored in this project enables the removal of the acetamide from C5 of sialic acid, enabling an easy and fast amidation of C5, saving four steps compared to the current synthetic pathway. However, side reactions made the synthesis of new compounds more difficult than expected, so just a few new compounds were observed in NMR and three were isolated. All in all, the reaction conditions, especially for the amidation and the processing of the reactions have to be optimized before simple synthesis is possible via this route.