Scalable Syntheses of the Vaulted Biaryl Ligands VAPOL and VANOL via the Cycloaddition/Electrocyclization Cascade

Synthetic approaches to the VANOL and VAPOL ligands are developed which are straightforward, inexpensive, efficient, and amenable to large-scale preparation of the ligands since minimum chromatographic purification is required. The key step in each synthesis is a cycloaddition/electrocyclic ring-opening/electrocyclic ring closure/tautomerization cascade that provides a direct one-step route to the monomers from which each ligand is prepared. Improved phenol coupling protocols are developed which provide the racemic ligands. Finally, dramatic improvements in the resolution procedures feature the reduction of the number of chemical steps and the defining of new crystallization protocols that greatly enhance the ease and reliability of the separation of diastereomeric salts.