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, CH 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.
Sung et al. (Thu,) studied this question.