Biologically Active Natural δ‐Lactones in Medicinal Chemistry: Structures, Bioactivities, and Synthesis

δ-Lactones are structurally diverse natural products broadly distributed across plants, fungi, microbes, and marine organisms. Their six-membered cyclic ester scaffold, often embedded in polyketide, terpenoid, fatty acid-derived, or hybrid frameworks, underpins wide-ranging pharmacological activities, including cytotoxic, antimicrobial, antiparasitic, and anti-inflammatory effects as well as modulation of enzymes and signaling pathways. Clinically relevant examples such as lovastatin, the first FDA-approved statin, and artemisinin, a cornerstone antimalarial, highlight the therapeutic value of δ-lactone motifs. In contrast, fostriecin and leptomycin B, though unsuccessful in the clinic, inspired analog development and validated new biological targets. Recent advances in synthesis-including ring-closing metathesis, CH lactonization, asymmetric annulations, and biomimetic approaches-have streamlined access to complex δ-lactones, enabling stereocontrolled synthesis and structure-activity relationship studies. This review provides a comprehensive overview of bioactive natural δ-lactones, organized by biosynthetic origin, and emphasizes their structural diversity, biological functions, and synthetic accessibility.