Catalyst‐Free Green Synthesis of Spirooxindole Pseudo‐Natural Products With Anti‐ROS and Cytoprotective Effects

The integration of sustainable synthesis with biological relevance is a key objective in contemporary medicinal chemistry. Herein, we report a catalyst-free, one-pot multicomponent protocol for the rapid synthesis of spirooxindole-based pseudo-natural products under mild and environmentally benign conditions. The reaction proceeds efficiently in methanol at room temperature, affording high yields (80%-90%) within 30 min without the need for external catalysts or chromatographic purification, highlighting its operational simplicity and scalability. Mechanistic studies suggest the in situ formation of a stable azomethine ylide, which undergoes a highly diastereoselective [3+2] cycloaddition and enables broad substrate tolerance across electron-deficient isatins and substituted maleimides. Biological evaluation using a methyl methanesulfonate-induced oxidative stress model in human lymphocytes revealed distinct structure-activity relationships. Compounds 4c and 4i significantly reduced intracellular reactive oxygen species and restored cell viability close to control levels, identifying them as promising antioxidative leads. Overall, this study demonstrates a sustainable approach to structurally diverse spirooxindole scaffolds with potential relevance to redox-associated pathologies.