GLYCOMIMETICS - A VERSATILE DE-NOVO SYNTHESIS OF BETA-1-C-ARYL-DEOXYMANNOJIRIMYCIN ANALOGS

The synthesis of 11 beta-1-C-aryl-deoxymannojirimycin analogues using a versatile de novo strategy is described. The origins of this report are derived from several recent developments in the area of C-1-substi tuted glycomimetic polyhydroxylated piperidines. This study is designe d as a structure-activity comparison to explore the effects of aryl su bstitution on the ability of the title compounds to inhibit glycosidas e enzymes. The polyhydroxylated piperidine ring was constructed using vinyl bromide 10, which was synthesized in six steps from the bromoben zene microbial oxidation metabolite bromo diol 9. A palladium-catalyze d Suzuki cross-coupling of vinyl bromide 10 and the corresponding aryl boronic acid served as the key pseudoanomeric carbon-carbon bond-formi ng step. Ozonolysis and selective reduction of the resultant carbonyl functions followed by reductive amination served to produce the azasug ar ring. The complete NMR analysis of the resultant piperidine ring st ereochemistry is also discussed. Fully deprotected beta-1-C-aryl-deoxy mannojirimycin analogues 8.HCl were obtained upon acidic deprotection.