Concise Biosynthesis of Phenylfuropyridones in Fungi

Phenylfuropyridone natural products from fungi exhibit a range of antibacterial and cytotoxicity activities, and can potentiate azole antifungal compounds. We elucidated the biosynthetic pathway of compounds in the citridone family through heterologous reconstitution of the pfp pathway. We demonstrate that multiple members of this family can be accessed from a reactive ortho‐quinone methide (o‐QM) intermediate through electrocyclization, cycloisomerization, or conjugate addition. Formation of the quaternary carbon center in citridone B is catalyzed by an epoxide‐forming P450 enzyme, followed by carbon skeletal rearrangement. Our results showcase how nature harvests the reactivities of an o‐QM intermediate to biosynthesize complex natural products. Phenylfuropyridone natural products have unique antibiotic activities, including potentiating azole activity and decreasing MRSA virulence. We elucidated the biosynthetic pathway of compounds in this family. From an ortho‐quinone methide intermediate, citridone A is formed nonenzymatically, whereas the quaternary carbon and 6‐6/5/5 ring system in citridone B are derived from a P450‐catalyzed oxidative rearrangement cascade.