Minor structural modifications of acyclic nucleoside phosphonates can dramatically affect their antiviral properties. This work discloses a shift in the selectivity spectrum of 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) nucleotides from herpesviruses toward hepatitis B virus (HBV) induced by their acyclic chain 2-substitution with a nonpolar group. Two series of racemic (<i>R</i>,<i>S</i>)-2-methyl-3-hydroxy-2-(phosphonomethoxy)propyl (MHPMP) and (<i>R</i>,<i>S</i>)-2-ethynyl-3-hydroxy-2-(phosphonomethoxy)propyl (EHPMP) nucleotides were initially synthesized. Among these, guanine-containing derivatives exhibited significant anti-HBV activities in the submicromolar range. Enantioenriched MHPMPG and EHPMPG analogues were subsequently obtained by Sharpless asymmetric epoxidation. The (<i>S</i>)-enantiomers possessed an 8- to 26-fold higher potency than the relative (<i>R</i>)-forms. A further comparison of the EC<sub>90</sub> values indicated that (<i>S</i>)-EHPMPG inhibited HBV replication more effectively than its 2-methyl analogue. A phosphonodiamidate prodrug of (<i>S</i>)-EHPMPG was thus prepared and found to exert a remarkably high anti-HBV activity (EC<sub>50</sub> = 9.27 nM) with excellent selectivity (SI<sub>50</sub> > 10,787), proving to be a promising candidate for anti-HBV drug development.