Synthesis of N-Glycans and Azasugars to Target Disease

Abstract

In this thesis two aspects of carbohydrate research will be discussed. First, the total synthesis of N-glycans found on allergens that are known to stimulate an allergic immune response and second, the synthesis of iminosugars in an attempt to extend the scope of the PGF-methodology. Asthma affects 235 million people worldwide, with New Zealand ranking among the highest in the world. Although there is a good understanding of how allergens trigger the immune system on a “macroscopic” level, how an allergen’s molecular structure causes such an allergic response remains unknown. Upon close review of carbohydrates present on the allergens that are known to give an allergic T helper (Th 2) immune response, a common structure has been identified. The structure consists of a complex type N-glycan made up of a pentasaccharide core (Man3(GlcNHAc)2), with additional 1,3-linked α-L-fucose and 1,2-linked D-xylose cappings. As part of a structure relationship study this heptasaccharide and structural derivatives thereof have been synthesised. The synthesis of these N-glycans will allow a more detailed study of the role of these defined structures in triggering an allergic immune response.

The second part of this thesis focuses on the protecting group free (PGF) synthesis of iminosugars, which are potent glycosidase inhibitors and are currently used in the treatment of a variety of diseases. Synthetic strategies for the synthesis of iminosugars involve the use of protecting groups, which are necessary to block potential competing reactive centres within a molecule during the multistep synthesis. The disadvantage, however, is that the installation of protecting groups introduces additional steps to the total synthesis, which inevitably leads to lower yields and the generation of waste. Within our group, PGF methodologies have been developed which allow for the synthesis of a variety of iminosugars. The work presented in this thesis extends the scope of this methodology for the synthesis of an important class of iminosugars, the 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidines. For the purpose of introducing an additional hydroxymethyl group, a ketose starting material was required, and therefore an efficient Vasella/reductive amination reaction using ketoses was developed. Additionally, iodocyclisation and carbamate annulation of the intermediate alkenylamines provided successful entry to the 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidines, exemplified by the efficient 6-step synthesis of 2,5-dideoxy-2,5-imino-L-iditol and 2,5-dideoxy-2,5-imino-D-mannitol (DMDP).