Seth B. Herzon

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.