The discovery of a novel route to highly substituted α-tropolones enables expedient entry to the core of the gukulenins.

A simple and general method for the synthesis of highly substituted α-tropolone ethers that allows rapid access to the bis(tropolone) core of the antiproliferative metabolites (-)-gukulenins A and F (3, 4) is described. The reaction proceeds by thermolytic opening of gem-dibromobicyclo[4.1.0]heptane intermediates, which are readily accessed from simple starting materials. Mechanistic studies suggest the reaction proceeds via an autocatalytic process mediated by methyl hypobromite. This synthetic sequence allows access to a broad array of highly substituted α-tropolones.