Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

We designed and synthesized helical short oligopeptides with an l-proline on the N-terminus and hydrocarbon stapling on the side chain. Side-chain stapling is a frequently used method for the development of biologically active peptides. Side-chain stapling can stabilize the secondary structures of peptides, and, therefore, stapled peptides may be applicable to peptide-based organocatalysts. Olefin-tethered cis-4-hydroxy-l-proline 1 and l-serine 2 and 8, and (R)-α-allyl-proline 18 were used as cross-linking motifs and incorporated into helical peptide sequences. The Z- and E-selectivities were observed for the ring-closing metathesis reactions of peptides 3 and 11 (i,i+1 series), respectively, while no E/Z-selectivity was observed for that of 19 (i,i+3 series). The stapled peptide B’ catalyzed the Michael addition reaction of 1-methylindole to α,β-unsaturated aldehyde, which was seven times faster than that of unstapled peptide B. Furthermore, the high catalytic activity was retained even at lower catalyst loadings (5 mol %) and lower temperatures (0 °C). The circular dichroism spectra of stapled peptide B’ showed a right-handed helix with a higher intensity than that of unstapled peptide B. These results indicate that the introduction of side-chain stapling is beneficial for enhancing the catalytic activity of short oligopeptide catalysts.