Direct Arylation of Juglone Enables Divergent Access to WS-5995 Analogs

The direct arylation of juglone enables concise access to WS-5995A and the related natural product WS-5995C, providing an entry to the WS-5995 family. The method affords access to lactam analogs via either C-2 or C-3 arylation, enabling the variation of the phenolic hydroxyl position. Cytotoxicity studies reveal a pronounced effect of the phenolic hydroxyl group positioning on biological activity, with the C-3-derived lactam showing enhanced potency. Further demethylation of WS-5995A increases activity, suggesting an important role of a free phenolic hydroxyl group.