Highly Enantioselective Organocatalytic Mannich Reaction of α-Benzylidene Succinimides with <i>N</i>-Boc Imines: Experimental and Theoretical Studies

The development of efficient and practical methods for the construction of chiral succinimide frameworks, which are the backbone of various natural products and widely studied in the field of pharmaceuticals, attracts considerable research attention. In this study, an asymmetric Mannich reaction of α-benzylidene succinimides with <i>N</i>-Boc imines was successfully performed using a bifunctional squaramide-type organocatalyst derived from quinine, affording the corresponding Mannich adduct with two contiguous stereocenters in high yields (up to 98%) with high diastereoselectivities (up to >20:1 dr) and excellent enantioselectivities (up to 99% ee). This protocol provides a direct approach to prepare chiral succinimide derivatives from simple starting material. Density Functional Theory (DFT) calculations with conformational search using an autosampling program revealed that the enantioselectivity profile was dominated by the deformation of the organocatalyst.