Peptide-Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C-Substituted Maleimides

Abstract

Catalytic stereoselective additions with maleimides are useful one-step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C-substituted. We present the tripeptide H-Pro-Pro-Asp-NHC12H25 as a catalyst for conjugate addition reactions between aldehydes and C-substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.