Synthesis of 5-fluoro N-acetylglucosamine glycosides and pyrophosphates via epoxide fluoridolysis: versatile reagents for the study of glycoconjugate biochemistry

Numerous carbohydrate-processing enzymes facilitate catalysis via stabilization of positive charges on or near the C-1, C-4, C-5, or C-6 positions. Substrate analogues differing only in the substitution of a fluorine for the axial C-5 hydrogen would possess reduced electron density at these positions and could be useful mechanistic probes of these enzymes. Introduction of this 5-fluoro substituent after radical halogenation was problematic because of the incompatibility of many protecting groups to the radical halogenation and the instability of the subsequent 5-fluoro hexosamines. Thus, to allow easy access to a wide variety of 5-fluoro glycosides and glycosyl phosphates, a versatile method for the introduction of the 5-fluoro group has been developed, the key step being the fluoridolysis of C-5, 6 epoxides. By use of this method, two fluorinated carbohydrates, uridine 5'-diphospho-5-fluoro-N-acetylglucosamine and octyl 5-fluoro-N-acetylglucosamine, have been synthesized. Initial biochemical investigations of these compounds show that 5-fluoro analogues are useful probes of transition-state charge development in several enzyme-catalyzed reactions.