Enantioselective Synthesis of Succinimides by Michael Addition of Aldehydes to Maleimides Organocatalyzed by Chiral Primary Amine‐Guanidines

Abstract

AbstractThe monoguanylation of (1S,2S)‐ and (1R,2R)‐cyclohexane‐1,2‐diamine affords chiral primary amine‐guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α‐disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N‐dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen‐bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine‐guanidines versus primary amine‐thioureas as the organocatalysts.