Chemical and Biosynthetic Evolution of Quadrane and Related Sesquiterpenoids

Abstract Natural products, with their potent bioactivities and selectivities, significantly benefit human health and agriculture. The evolution of biosynthetic enzymes of natural products has greatly expanded their chemical space relevant to bioactivity. Insights from natural evolution provide valuable guidance for engineering these enzymes to create molecules with novel structures and bioactivities. Recent studies have unveiled an intriguing biosynthetic evolution of fungal‐derived quadrane sesquiterpene scaffolds, indicating evolutionary relationships among sesquiterpene scaffolds such as humulene, caryophyllene, presilphiperfolan‐8‐ol, silphinene, and terrecyclene, rooted in their biosynthetic mechanisms. This review summarizes recent progress in the discovery and biosynthetic characterization of these sesquiterpenoids. These findings illuminate the logic behind the chemical and biosynthetic evolution of sesquiterpenes and offer opportunities to discover new sesquiterpenoids through genome mining.