Total Synthesis of Gracilioether F: Development and Application of Lewis Acid Promoted Ketene-Alkene [2+2] Cycloadditions and Late-Stage C-H Oxidation

The first synthesis of gracilioether F, a polyketide natural product with an unusual tricyclic core and five contiguous stereocenters, is described. Key steps of the synthesis include a Lewis acid promoted ketene-alkene [2+2] cycloaddition and a late-stage carboxylic acid directed C(sp(3))-H oxidation. The synthesis requires only eight steps from norbornadiene.