Three-component assembly and structure-function relationships of (-)-gukulenin A.

α-Tropolones comprise an unsaturated seven-membered ring bearing a hydroxyl substituent adjacent to a polarized carbon-oxygen π bond. This polarization imparts a permanent molecular dipole and aromatic stabilization to the ring, resulting in distinct physical properties, including affinity for divalent metals and ambiphilic reactivity. Among secondary metabolites that contain α-tropolones, the pseudodimeric isolate (-)-gukulenin A (7) stands out for its complexity and has shown promise in treating mouse models of ovarian cancer. In this study, we describe an enantioselective synthesis of (-)-gukulenin A (7). Key steps include a directed C-H arylation, a tandem Grob fragmentation-alkylation, an innovative synthesis of methyl tropolone ethers, a multicomponent cross-coupling, and a thermal carbonyl-ene reaction. Structure-function studies establish the dimeric tropolone and aldehyde substructures as drivers of cytotoxicity.