Synthesis of Collinoketones via Biomimetic [6 + 4] Cycloaddition

Cycloadditions are among the most powerful reactions for constructing molecular complexity. The archetypal example is the [4 + 2] (Diels-Alder) cycloaddition, which efficiently furnishes cyclohexene derivatives. In comparison, the [6 + 4] cycloaddition, which forms cyclodecatriene derivatives from triene and diene reactants, is far less common. Here, we report a short and stereoselective synthesis of a highly unsaturated macrolactone that has been proposed as a biosynthetic precursor of the tricyclic cyclodecatriene collinoketone A and the neuroprotective natural product collinolactone. We find that this macrolactone undergoes effective transannular [6 + 4] cycloadditions to afford stereoisomers of collinoketone A, which we name collinoketones B and C. Our work reassigns the structure of the natural product reported as collinoketone A and highlights the complexity of [6 + 4] cycloadditions with conformationally flexible substrates.