The development of synthetic methodology for stereoselective synthesis of aminoglycosides

• Main Author: Simon, Binto
• Other Authors: Berrisford, David
• Published: University of Manchester 2013
• Subjects: 572.886
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.574302

RNA is recognised as an important biomolecule involved in many broad cellular functions such as transcription, translation regulation and protein synthesis. Most pathogenic viruses replicate their genome as RNA during some stages in their life cycle. There is an urgent need to develop new methods to treat numerous viral diseases by targeting RNA and to understand the processes by which RNA-protein complexation can be inhibited. Our study focuses on the interactions between the HIV-1 Rev Responsive Element RNA (RRE) with a series of aminoglycosides developed jointly between our group in Manchester and GSK (USA). Even though a number of novel aminoglycoside have been explored previously, they are complex, large molecular weight compounds with low specificity, which limits their use as RNA recognition ligands and anti-viral drugs. The key problem is to be able to synthesise precursors by short, direct routes, avoiding significant detours caused by traditional carbohydrate protecting group strategies, while still delivering sterocontrol and opportunities to diversify. In chapter II we describe our efforts to synthesize the 6-glucosamine moiety (A-ring). A flexible synthesis of 6-aminoglucosamine derivatives can be accomplished in 5 steps using a totally regioselective enzymatic hydrolysis, controlled oxidation to sensitive but manageable aldehydes (hitherto rarely accomplished with a C-4 OAc), and reductive amination technology that allow for unprecedented diversification. In a different approach stereocontrolled synthesis of a model compound was achieved in 4 steps including a novel TEMPO oxidation and a one-pot oxidation/imine-reduction for the complete synthesis of the molecule.Chapter III describes our attempts towards the development of a robust stereoselective O-glycosylation strategy using Lewis acids. In pursuance of an efficient synthesis of our designed RNA binder target compound the stereoselective formation of the glycosidic linkage connecting the A-ring with the 2-DOS ring is an important step. This chapter also gives a general overview of the challenges involved in glycosylation followed by the strategies we employed to overcome some of these issues. We discuss our unusual stereocontrolled glycosylation in which, despite a neighbouring “participatory” group at C-2, the α-glycoside is delivered in high yield. This result implies that the reaction does not occur through a conventional neighbouring group participation.