Chloropupukeananin, chloropupukeanolides, and chloropestolides are a family of structurally complex bioactive natural products that possess highly functionalized tricyclo­[4.3.1.03,7]­decane or bicyclo[2.2.2]­octane skeletons. Biosynthesis of the chloropupukeananin family is triggered by the intermolecular heterodimeric Diels–Alder reaction between maldoxin and iso-A82775C; however, the enzymes involved have not yet been identified. We herein report the one-pot biomimetic synthesis of chloropupukeananin and chloropupukeanolide D. Moreover, the effect of the solvent on the intermolecular Diels–Alder reaction of siccayne and maldoxin suggested that the biosynthesis of the chloropupukeananin family involves a Diels–Alderase-catalyzed heterodimeric Diels–Alder reaction.

Ent‐kaurenes consist of an ABC‐ring based on a trans‐anti‐hydrophenanthrene skeleton and a D ring with an exomethylene. Highly oxygen‐functionalized ent‐kauren‐15‐ones have promising antiinflammatory pharmacological activity. In this study, we developed a novel diastereoselective synthesis of trans‐anti‐hydrophenanthrenes via a Ti‐mediated reductive radical cyclization. We also demonstrated the applicability of this method by developing the first total synthesis of (±)‐kamebanin (longest linear sequence; 17 steps, overall yield; 6.5 %). Furthermore, this synthesis provided a formal semi‐pinacol rearrangement for the construction of the quaternary carbon at C8 and a novel Thorpe‐Ziegler‐type reaction for the construction of the D‐ring.

The biomimetic total synthesis of (+)-chloropupukeananin (overall 4.5% yield, 19 steps from pyrone <b>22</b>) and (−)-chloropupukeanolide D via an intermolecular Diels-Alder reaction using (−)-maldoxin and (+)-iso-A82775C and an intramolecular carbonyl-ene reaction has been achieved. Moreover, the biomimetic synthesis of chloropestolides H-K using (−)-maldoxin and siccayne unveiled the solvent effect of the intermolecular Diels-Alder reaction. The origin of the stereoselectivity of the intermolecular Diels-Alder reaction is still elusive; however, the biosynthesis of the chloropupukeananin family should involve enzymes that catalyse the intermolecular Diels-Alder reaction.