Diastereoselective Cascade Double Michael Addition to Access Bridged Coumarins, Oxindoles and Spirooxindoles: A Sustainable Strategy for Synthesis of Anticancer Molecules

An efficient and concise synthesis of highly functionalized bridged coumarins has been developed through a diastereoselective double Michael addition reaction of p‐quinols with various 4‐hydroxy coumarins under catalyst‐free conditions in H2O‐DMSO (8:2). The method has been applied to oxindoles for the synthesis of a variety of bridged‐oxindoles and bridged‐spiroxindoles in presence of a DABCO base using H2O‐EtOH (8:2) as solvent medium. The strategy is simple, highly atom economical as there is no by‐product and environmentally benign (E‐factor = 0.1‐0.9). The synthesized compounds were screened against triple‐negative breast cancers and found that bridged coumarin (3a) and oxindole (5d) compounds exhibit potent anti‐cancer activity at 6.6 and 8.8 µM (IC50) concentrations respectively. Further analysis revealed that 3a and 5d caused elevated early and total apoptosis by arresting the MDA‐MB‐468 cells in G2/M phase of the cell cycle. Overall, our results demonstrate that bridged coumarin (3a) and oxindole (5d) compounds‐based approach attenuates the cancer progression and may pave a path for the translational outcome.