Synthesis of Iminosugar C-Glycosides via Tandem Allylic Azide Rearrangement - Huisgen Cycloaddition

Abstract

Iminosugars are naturally occurring polyhydroxylated alkaloids. These natural mimics of carbohydrates have found clinical use with their biological activity mainly attributed to their inhibition of glycoprocessing enzymes. The background to this thesis and the intramolecular tandem allylic azide rearrangement -- Huisgen cycloaddition are discussed in Chapter 1. Chapter 2 describes the synthesis of iminosugar derivatives from D-glucono-[delta]-lactone which is an extension of work carried out previously in the Murphy group for the preparation of 1-deoxyiminosugars. This route was particularly successful in the highly stereoselective preparation of iminosugars fused to triazoles from an intramolecular rearrangement-cycloaddition between azide and alkyne groups. However the rearrangement-cycloaddition between azide and alkene groups based on intermediates with the glucose configuration suffered from poor yields. An alternative route using a zinc-mediated reductive fragmentation reaction from a variety of commercially available sugars to prepare allylic azide precursors was next explored. This is discussed in Chapters 3-5, which also describe the rearrangement-cycloaddition reactions of these intermediates which lead to iminosugars based on glucose, mannose and galactose. The importance of a conformational constraint to achieve the cycloaddition emerged. Again, the cycloaddition of the glucose intermediates was affected by poor yields. However, results with the mannose and galactose derivatives were more promising. The stereoselectivity was assigned using NMR coupling constants (JH1-H2 and JC1-H1 values), NOEs, X-ray crystallography and comparisons with analytical data for compounds already described in the literature. The stereoselectivities were rationalised with the aid of models built using molecular mechanics. The synthesis of a natural C-glycoside iminosugar was achieved. Overall this thesis demonstrates that an allylic azide rearrangement carried out in tandem with Huisgen cycloaddition is diastereoselective in ring formation and should be useful in organic chemistry.