Total Synthesis of (±)-Dhilirolide U

We report the first total synthesis of (±)-dhilirolide U, a highly oxidized meroterpenoid featuring a densely functionalized 6/6/6/5/5-pentacyclic skeleton. Central to the strategy are a MnIII-mediated cyclization sequence and a Payne-type rearrangement cascade, which together forge a bicyclo[3.2.1]octane fused to a γ-lactone─the defining motif of the dhilirolide natural product family. Both transformations proceed in high yields and with excellent diastereocontrol. Intramolecular Ni-catalyzed conjugate addition was leveraged to install the vicinal quaternary carbon centers. This transformation set the stage for construction of the tetrahydroisochromenone subunit and completion of (±)-dhilirolide U. The reported route to the highly decorated bicyclo[3.2.1]octane provides a blueprint to access the diverse family that are the complex dhilirolide meroterpenoids.