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

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-NHC12 H25 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.

Crystal structures of peptidic catalysts of the H-dPro-Pro-Xaa type.

Crystal structures of catalytically active tripeptides of the general type H-dPro-Pro-Xaa and related N-acetylated analogs were compared. The influence of acylation at the N-terminus, the nature of the C-terminal residue, coordinating groups, and intramolecular hydrogen bonds on the conformation of the tripeptides was examined. Regardless of the presence or absence of stabilizing intramolecular H-bonds or n → π* interactions, all of the analyzed peptides share a ß-turn-like conformation, which highlights the structural rigidity of the dPro-Pro motif and its value for conformational preorganization. The C-terminal residues and coordinating moieties were found to affect the turn-conformation, which suggests that H-dPro-Pro-Xaa type peptides are sufficiently flexible to adopt distinctly different but related conformations.

Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide.

The tripeptide H-dPro-Pro-Asn-NH2 is presented as a catalyst for asymmetric conjugate addition reactions of aldehydes to maleimide. The peptidic catalyst promotes the reaction between various aldehydes and unprotected maleimide with high stereoselectivities and yields. The obtained products were readily derivatized to the corresponding pyrrolidines, lactams, lactones, and peptide-like compounds. (1) H NMR spectroscopic, crystallographic, and computational investigations provided insight into the conformational properties of H-dPro-Pro-Asn-NH2 and revealed the importance of hydrogen bonding between the peptide and maleimide for catalyzing the stereoselective C-C bond formation.