Bromoetherification-based strategy towards the spirocyclic chromophore of chlorofusin

A short and direct route to the racemic model chromophore of the potent p53-MDM2 antagonist, chlorofusin, is presented. The spirocyclic chromophores were successfully constructed in high yields by an NBS-mediated intramolecular haloetherification. Ring expansion was observed in the subsequent reaction of the bromides with silver nitrate in refluxing acetone and water. Conversion of the bromides to the desired ketones was finally achieved by NMO oxidation. All four possible isomeric chromophores were finally synthesized and unambiguously characterized by X-ray crystallography studies.