Ten-membered lactones (TMLs) produced by phytopathogenic fungi are considered model compounds for the development of nature-inspired agrochemicals with novel mechanisms of action. Despite their structural simplicity, TMLs display a broad range of biological activities. Although total synthesis methods for many TMLs have been developed, systematic data on their chemical properties remain highly limited. To address this gap, we investigated the reactivity of herbarumin I, 2-epi-herbarumin II, stagonolides J and K, pinolidoxin, and their C-7 oxidized analogs in oxidation, hydrogenation, and isomerization reactions. We demonstrate that their spatially constrained architecture and functional group topology promote distinctive and reproducible reactivity patterns, including stereospecific epoxidation at the C5–C6 bond, mild oxidative cleavage at C7–C8, Pd/Pt-catalyzed allylic transposition, transannulation to chromone derivatives, and base-induced dimerization into fused tetrahydrofuran scaffolds. As a result, 31 new compounds were synthesized, three new reactions were discovered with mechanistic insights provided, and the absolute configuration was established for stagonolide J and stagochromene A and revised for 5,6-epoxypinolidoxin. Preliminary conclusions were drawn about the chemical lability of unsaturated C7-keto derivatives of TMLs in protic media. Such mapping of structure–reactivity relationships within this subclass of TMLs provides a foundation for future semisynthetic derivatization, chemical stability assessment, and rational expansion of biologically relevant scaffolds. © 2026 American Chemical Society and American Society of Pharmacognosy