Recent advances in the total synthesis of highly strained tetracyclic diterpenoids from Euphorbiaceae: Pepluanols and Euphorikanin A

Euphorbiaceae -derived highly strained tetracyclic diterpenoids represented by Pepluanols A–D and Euphorikanin A are a class of natural products with novel skeletons, complex stereostructures, and prominent biological activities, which have become a research hotspot in the fields of organic synthesis and medicinal chemistry. Their unique ring–fusion modes, densely arranged contiguous chiral centers, highly sterically congested molecular frameworks, and scarce natural abundance pose tremendous challenges to chemical synthesis. Meanwhile, their specific inhibitory effects on ion channels and selective cytotoxicity against cancer cells endow them with significant pharmaceutical development potential. This review systematically summarizes the latest research progress in the total synthesis of Pepluanols and Euphorikanin A in recent years, elaborates in detail the design ideas, key reactions, stereocontrol strategies, and synthetic innovations of different synthetic routes for these target molecules, and analyzes the advantages and limitations of various synthetic methods. The core synthetic challenges of this class of diterpenoids are summarized from the aspects of polycyclic framework construction, chiral center control, unconventional ring system assembly, and oxidation-state modulation. Furthermore, the unresolved scientific issues in the current synthetic research are discussed, and the future research directions are prospected in combination with the development trends of modern organic synthetic chemistry, such as photocatalysis/transition-metal synergistic catalysis, biomimetic synthesis, and modular synthesis. This review provides a comprehensive reference for the synthesis of complex Euphorbiaceae diterpenoids (Pepluanols and Euphorikanin A) and lays a foundation for their structural modification and drug development.