Influence of the &ITTrans&IT/&ITCis&IT Conformer Ratio on the Stereoselectivity of Peptidic Catalysts

Trans/cis isomerization of Xaa-Pro bonds is key for the structure and function of several enzymes. In recent years, numerous versatile peptidic catalysts have been developed that bear Xaa-Pro amide bonds. Due to the many degrees of freedom within even short peptides, the design and optimization of peptidic catalysts by rational structural modifications is difficult. We envisioned that control over the trans/cis amide bond ratio may provide a tool to optimize the catalytic performance of peptidic catalysts. Here, we investigated the influence of the amide bond conformation on the stereoselectivity of H-Pro-Pro-Xaa-NH2-type peptidic catalysts in conjugate addition reactions. The middle Pro residue within the tripeptides was replaced with analogues of varying ring sizes (azetidine carboxylic acid, Aze, and piperidine carboxylic acid, Pip) to produce different trans/cis ratios in different solvents. The studies revealed a direct correlation between the trans/cis amide bond ratio and the enantio- and diastereoselectivity of structurally related peptidic catalysts. These insights led to the identification of H-D-Pro-Pip-Glu-NH2 as a highly reactive and stereoselective amine-based catalyst that allows C-C bond formations to be performed in the presence of as little as 0.05 mol %, which is the lowest catalyst loading yet achieved for organocatalyzed reactions that rely on an enamine-based mechanism.