Synthesis of orthogonally protected 2‐silyl nucleosides were achieved by trans opening of sugar epoxides with nucleobases catalyzed by trimethylsilyltrifluoromethanesulfonate using hexamethyldisilazane both as solvent and silylating agent. Both α and β nucleosides were obtained with complete stereocontrol only by changing the epoxide stereochemistry. The synthesized nucleosides exist in different chair conformations depending upon the nature of protecting groups present in the sugar moiety as determined from coupling constants in the proton NMR. All the synthesized nucleosides were screened for biofilm inhibition activity against four bacterial pathogens and compound 7c was found to be most potent against Salmonella typhimurium with 1.22 µm biofilm inhibitory activity taking ciprofloxacin as control.