ABSTRACT
Highly ( Z)-diastereoselective approaches for the synthesis of trifluoromethylated exo-glycals by copper and photoredox catalysis are described. These complementary reactions are applicable to a wide range of methylene exo-glycals generated from the corresponding pyranoses and furanoses and give trifluoromethylated compounds under mild conditions in moderate to good yields. DFT calculations have allowed a rationalization of the observed ( Z)-stereoselectivity.
ABSTRACT
This study reports a new methodology to synthesize exo-glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo-glycals displaying two electron-withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z/E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo-glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)-galactofuranose analogues. These two Z/E isomers were evaluated as inhibitors of UGM, GlfT1, and GlfT2, the three mycobacterial galactofuranose processing enzymes. Molecule 46-(E) is the first characterized inhibitor of GlfT1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, GlfT2 showed a better affinity for the (Z) isomer. The three enzymes studied in the present work are not only interesting because, mechanistically, they are still the topic of intense investigations, but also because they constitute very important targets for the development of novel antimycobacterial agents.
