A New Methodology for the Synthesis of Fluorinated exo-Glycals and Their Time-Dependent Inhibition of UDP-Galactopyranose Mutase

摘要

Fluorinated carbohydrates constitute a very important class of mechanistic probes for glycosyl-pro-cessing enzymes.In this study,we describe the first synthesis of fluorinated and phosphonylated exo-glycals and their corresponding nucleotide sugars in the galactofuranose series.The synthetic protocol that we have developed is a Selectfluor-mediated fluorination/ elimination sequence on phosphonylated exo-glycals,and it offers a new entry into fluorinated carbohydrate chemistry.The challenging E/Z stereochemi-cal assignment of the resulting tetra-substituted alkenes,which bear an alkoxy,an alkyl,a fluoro,and a phos-phonyl group,has been achieved through NMR experiments.The corresponding (E)- and (Z)-nucleotide fluo-rosugars have been prepared and tested as inhibitors of UDP-galactopyr-anose mutase (UGM).UGM is a fla-voenzyme that catalyzes the isomeriza-tion of uridine diphosphate(UDP)-gal-actopyranose into UDP-galactofura-nose,a key step of the biosynthesis of important mycobacterial cell-wall gly-coconjugates.The two diastereomeric molecules were found to display time-dependent inactivation of UGM,as expected from preliminary results using non-fluorinated exo-glycal nucleotides.The inhibitory properties of the two fluorinated molecules led us to suggest that the inactivation mechanism proceeds through two-electron processes,despite the presence of the flavin co-factor within the UGM catalytic site.