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.

Importance of dipole moments and ambient polarity for the conformation of Xaa-Pro moieties - a combined experimental and theoretical study.

NMR spectroscopic studies with a series of proline derivatives revealed that the polarity of the environment has a significant effect on the trans : cis isomer ratio of Xaa-Pro bonds. Computational studies showed that this effect is due to differences in the overall dipole moments of trans and cis conformers. Comparisons between the conformational properties of amide and ester derivatives revealed an intricate balance between polarity effects and n → π* interactions of adjacent carbonyl groups. The findings have important implications for protein folding and signaling as well as the performance of proline-based stereoselective catalysts.

Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT).

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.