Application of Ni/Zr-Mediated Ketone Coupling for the Scalable Synthesis of Homohalichondrin B.

A practical and improved synthetic route for the scalable synthesis of homohalichondrin B has been developed. Formation of the highly stereoselective [6,6]-spiroskeleton system through a convergent Ni/Zr-mediated ketone coupling, followed by acid-promoted spiroketalization, simplified the route considerably. Higher coupling efficiency was achieved by fine-tuning the Ni/Ni (1:50) catalyst loadings with an equimolar (1:1) mixture of coupling partners.