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.