Coupling of Sterically Hindered Trisubstituted Olefins and Benzocyclobutenones by CC Activation: Total Synthesis and Structural Revision of Cycloinumakiol

The first total syntheses of the proposed structure of cycloinumakiol (1) and its C5 epimer (18) are achieved in a concise and efficient fashion. Starting from the known 3-hydroxybenzocyclobutenone, 1 and 18 are obtained in nine and five steps with overall yields of 15% and 33%, respectively. The key for the success of this approach is the use of a catalytic C-C activation strategy for constructing the tetracyclic core of 1 through carboacylation of a sterically hindered trisubstituted olefin with benzocyclobutenone. In addition, the structure of the natural cycloinumakiol was reassigned to 19-hydroxytotarol (7) through X-ray diffraction analysis. This work demonstrates the potential of C-C activation for streamlining complex natural product synthesis.