Design and Synthesis of Helical -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 -4-hydroxy-L-proline and L-serine and , and ()-α-allyl-proline were used as cross-linking motifs and incorporated into helical peptide sequences. The - and -selectivities were observed for the ring-closing metathesis reactions of peptides and (,+1 series), respectively, while no /-selectivity was observed for that of (,+3 series). The stapled peptide catalyzed the Michael addition reaction of 1-methylindole to α,β-unsaturated aldehyde, which was seven times faster than that of unstapled peptide . 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 showed a right-handed helix with a higher intensity than that of unstapled peptide . These results indicate that the introduction of side-chain stapling is beneficial for enhancing the catalytic activity of short oligopeptide catalysts.