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

(–)-Gukulenin A is a cytotoxic secondary metabolite that bears two aromatic α-tropolone residues, 10 asymmetric stereocenters, functionalized cyclopentane fragments, a labile hemiketal, and an electrophilic aldehyde. Here we describe an enantioselective synthesis of (–)-gukulenin A (7) by a three-component assembly strategy. Key steps include the directed C–H arylation of a norbornyl picolinamide, a tandem Grob fragmentation–alkylation, a novel method for the synthesis of α-tropolones, a site-selective, multicomponent cross-coupling reaction, and a thermal carbonyl–ene reaction to complete the carbon skeleton. (–)-Gukulenin A (7) is efficacious and well-tolerated in murine models of ovarian cancer. Structure–function studies establish the dimeric tropolone and aldehyde substructures within (–)-gukulenin A (7) as critical drivers of cytotoxicity.