Chiral syntheses of a series of hexahydroisobenzofuran (HIBF) nucleosides have been accomplished via glycosylation of a stereo-defined (syn-isomer) sugar motif with the appropriate silylated bases. All nucleoside analogues were obtained in 52-71% yield as a mixture of alpha- and beta-anomeric products increasing the breadth of the novel nucleosides available for screening. Nucleoside derivatives were tested as inhibitor of HIV-1 in human peripheral blood mononuclear (PBM) cells.