What question did this study set out to answer?

The aim is to achieve the total synthesis of (±)-dhilirolide U, a complex meroterpenoid with a defined structure.

February 11, 2026Journal of the American Chemical Society2 citations

Total Synthesis of (±)-Dhilirolide U

HWHenrik R. WilkeETH Zurich MFMarlene FadelETH Zurich KPKacper J. PatejRoche (Switzerland)

Key Points

The aim is to achieve the total synthesis of (±)-dhilirolide U, a complex meroterpenoid with a defined structure.
Utilized Mn<sup>III</sup>-mediated cyclization for bicyclo[3.2.1]octane formation.
Employed a Payne-type rearrangement for structural construction.
Implemented Ni-catalyzed conjugate addition to add vicinal quaternary carbon centers.
Constructed the tetrahydroisochromenone subunit as part of the synthetic route.
Achieved high yields and excellent diastereocontrol in key transformations.
Successfully constructed the bicyclo[3.2.1]octane fused to a γ-lactone.
Completed the synthesis of (±)-dhilirolide U, validating the synthetic strategy.

Abstract

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 bicyclo3.2.1octane 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 bicyclo3.2.1octane provides a blueprint to access the diverse family that are the complex dhilirolide meroterpenoids.

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