Bicyclic δ-Thiolactone Glycomimetics: Stereoselective Synthesis and Discovery of Stereocontrolled Antiphage Activity

A stereocontrolled synthesis of bicyclic thiolactones from methyl α-mannopyranoside and methyl α-galactopyranoside was achieved via iodination, selective protection, Bernet-Vasella fragmentation, and Knoevenagel-hetero-Diels-Alder domino reaction under polar, anhydrous, and inert conditions. d-mannoside derivatives cyclized with complete diastereoselectivity, whereas d-galactoside analogues showed substituent-dependent stereochemical outcomes. Structural assignments were confirmed by two-dimensional NMR spectroscopy and X-ray analyses. Spontaneous tautomerization of thioamides generated C═N bonds and new stereocenters, providing a predictable route to carbohydrate-derived thiolactones. Among the synthesized compounds, thiolactone 29 selectively inactivated bacteriophage T4 (>2-log reduction in PFU) without affecting Escherichia coli viability. These results demonstrate that stereochemical control dictates antiphage activity, establishing a framework for designing selective, non-toxic virucidal agents.