Dhilirolide U is a highly oxygenated fungal meroterpenoid derived from 3,5-dimethylorsellinic acid (DMOA). Its unique 6/6/6/5/5 pentacyclic framework, featuring a densely functionalized bicyclo[3.2.1]octane core fused to a γ-lactone, presents significant challenges for chemical synthesis. In 2026, Carreira and coworkers reported the first total synthesis of (±)-dhilirolide U, employing a series of strategically designed transformations to construct its complex molecular architecture. A key step involves a manganese(III)-mediated oxidative radical cyclization that efficiently assembles the bicyclo[3.2.1]octane core with excellent diastereoselectivity. An acid-mediated Payne-type rearrangement subsequently establishes the characteristic γ-lactone framework. Another significant transformation is a nickel-catalyzed intramolecular conjugate addition that enables the construction of adjacent quaternary carbon centers within a sterically congested environment. Further functional group transformations, including intramolecular aldol condensation and palladium-catalyzed Stille cross-coupling, complete the synthesis. This seminar will highlight the synthetic strategy, key reaction mechanisms, reagent selection and stereochemical control underlying this achievement, while discussing the challenges and broader significance of these transformations in complex natural product synthesis.
 

Reference: Wilke, H. R. et al. J. Am. Chem. Soc. 2026, 148, 5916–5922. https://doi.org/10.1021/jacs.5c22734