Certain 2',3'-dideoxynucleosides (e.g., AZT, DDI, DDC) are clinically used for HIV-1 treatment due to their in vivo phosphorylation to 5'-triphosphates that inhibit reverse transcriptase, but their side effects (e.g., bone marrow suppression, pancreatitis, peripheral neuropathy) and the emergence of resistant strains have prompted the search for more potent, less toxic, and non-cross-resistant agents. Given the interesting properties of compound 1 and its enantiomers, we prepared a series of uracil- and cytosine-substituted oxathiolane analogues to evaluate their anti-HIV activity and cytotoxicity using our previously developed synthetic route for BCH-189. Stannic chloride as a Lewis acid catalyst enabled complete β-selectivity (>95%) in the glycosylation of the oxathiolane ring, and this stereoselectivity was supported by a tin-sulfur complexation mechanism—evidenced by 13C NMR chemical shift changes of tetrahydrothiophene and 2-methyloxathiolane in the presence of stannic chloride (a soft Lewis acid, whereas the hard Lewis acid trimethylsilyl triflate had no effect). Additionally, since HBV encodes a reverse transcriptase, we assessed the anti-HBV activity of these analogues. The (-)-enantiomers of 1a and 1c exhibited potent anti-HIV activity with EC50 values of 9 and 10 nM, respectively. While several derivatives (e.g., 1d, 1e, 1f, 2c, 2d) showed modest anti-HBV activity (e.g., 87% inhibition at 10 µM for 1d), none were as potent as 1a and 1c. In summary, we validated the generality of our synthetic approach for oxathiolane nucleosides, provided strong evidence for the role of tin-sulfur complexes in controlling glycosylation stereoselectivity, and identified BCH-189 (parent cytosine oxathiolane) and FTC (5-fluoro derivative) as the most promising candidates with favorable anti-HIV activity and low cytotoxicity.