Enantioselective Construction of Cyclic Enaminone-Based 3-Substituted 3-Amino-2-oxindole Scaffolds via Catalytic Asymmetric Additions of Isatin-Derived Imines

The first catalytic asymmetric construction of the cyclic enaminone-based 3-substituted 3-amino-2-oxindole scaffold with potential bioactivity has been developed via chiral phosphoric acid-catalyzed enantioselective addition reactions of cyclic enaminones to isatin-derived imines, which afforded a series of cyclic enaminone-based 3-substituted 3-amino-2-oxindoles in high yields and excellent enantioselectivities (up to 99% yield, 97% ee). The investigation of the reaction mechanism suggested that it was facilitated by a dual hydrogen-bonding activation mode between the two substrates and the chiral phosphoric acid. Besides, this method could be utilized for a large-scale synthesis with maintained enantioselectivity. This approach will not only offer a useful method for enantioselective construction of the cyclic enaminone-based 3-substituted 3-amino-2-oxindole scaffold, but also enrich the research on catalytic asymmetric addition reactions of isatin-derived imines by using electron-rich olefins as nucleophiles. More importantly, a preliminary evaluation on the cytotoxicity of some selected products revealed that two of the enantio-pure compounds exhibited moderate to strong cytotoxicity to A549, 7860, ECA109 and BT474 cancer cell lines.