Enantioselective Preparation of Chiral Succinimide Derivatives by Organocatalytic Michael Addition

Abstract: Chiral succinimide derivatives are privileged scaffolds in bioactive compounds and pharmaceuticals. In this study, a novel class of bifunctional thiourea catalysts derived from isosteviol and a chiral 1,2-diphenylethylenediamine scaffold was synthesized and applied in the enantioselective Michael addition of aldehydes to maleimides. Under optimized conditions in CH₂Cl₂ at room temperature, a broad range of succinimide derivatives were obtained in high yields (82–97%) with excellent enantioselectivities (up to 99% ee). Both enantiomers of the adducts were accessible by switching between the two catalyst configurations. The substrate scope accommodated various N-aryl maleimides bearing electron-donating or electron-withdrawing groups, as well as alicyclic aldehydes. The reaction was scalable to gram level without loss of efficiency. A plausible enamine-based catalytic mechanism involving dual activation by the thiourea moiety is proposed. This protocol represents a significant advancement in the synthesis of chiral succinimides, offering a robust and scalable route to these valuable intermediates for drug discovery and expanding the utility of isosteviol-based organocatalysts.