Carbohydrates as precursors to macrocyclic and iminosugar frameworks

Abstract

Natural products have been perceived as privileged structures in drug discovery based on their evolutionary experience. Chapter 1, explores previous exploitation of this platform by medicinal chemists to identify some potent inhibitors of tumour cell migration, including migrastatin and isomigrastatin. Other analogues of these 14- and 12-ring frameworks have been prepared based on both, quinic and glucuronic acid. These derivatives have shown promise as potent inhibitors of tumour cell migration. Chapter 2 describes the synthesis of novel macrocyclic frameworks structurally related to glucuronic acid. A Lewis-acid induced anomerisation of the β- to the corresponding α-anomer, was vital in the preparation of the α-macrocycles. The macrolactams prepared were biologically evaluated and a couple of key compounds found to be potent inhibitors of tumour cell migration. Chapter 3 introduces iminosugars, a class of natural products known for their broad therapeutic potential. This work focuses on the allylic azide rearrangement and Huisgen cycloaddition, which together can provide access to nitrogen-containing frameworks from D-mannose. Chapter 4 outlines difficulties in relation to stereochemical assignment, from the formation of two new stereocentres in this diastereoselective reaction resulting in piperidine C-glycosyl iminosugars. This work, based on previous studies, required an innate conformational restraint in the form of an isopropylidine group for a successful cycloaddition. Chapter 5 explores enforcement of the tandem rearrangement-cycloaddition to prepare C-glycosyl pyrrolidines. Contradictory to previous reports, removal of the isopropylidine restraint enhanced the cyclisation resulting in improved selectivity, yield and reaction times. This work also showed regioselectivity was also an important factor in the tandem cycloaddition. Chapter 6 explores employment of similar methodology for the preparation of α,α-disubstituted quaternary iminosugars, reiterating success of the cycloaddition (with improved selectivity, yield and reaction times) in absence of a conformational restraint. Studies of the alkene-azide vs. alkyne-azide reactivity were also explored, identifying two novel triazole-fused scaffolds. The stereoselectivities of the nitrogen-containing products (Chapters 4-6) were all assigned by Nuclear Overhauser Spectroscopy experiments. Further clarification by observation of 1H NMR J values (J1,2, J4,5), X-ray crystallography and comparisons with available literature analytical data were also made where possible.