Formation of Fungal 2,18-Dioxo-2,18-seco Indole Diterpenes by Nonenzymatic Flavin-Catalyzed Oxidative Ring Expansion and Oxygen Incorporation from Solvent Water

Most naturally occurring indole diterpenes share a 6/5/5/6/6/6 hexacyclic ring system, while a 6/8/6/6/6 pentacyclic skeleton is occasionally observed. In this study, we demonstrate the formation of an eight-membered C-N heteroring via nonenzymatic flavin-catalyzed oxidative indole ring opening. More interestingly, ¹⁸O-labeled experiments proved that the two incorporated oxygen atoms are predominantly originated from water instead of molecular oxygen. In this process, the oxidized form of flavin catalyzes two successive oxidations of amines to imines with involvement of hydrolysis for the ring expansion. The reduced flavin is then regenerated by oxidation with molecular oxygen to form H₂O₂.