Abstract
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.
Highlights
Hydrocarbon stapling is one of the most commonly used methods to stabilize the secondary structure of peptides as a way to provide enhanced functionality [1,2,3]
This powerful tool is especially important for short oligopeptides due to their flexible secondary structure
Grubbs et al reported the synthesis of 310 -helical heptapeptides stabilized by hydrocarbon stapling at the i,i+4 positions using ring-closing metathesis [4,5]
Summary
Hydrocarbon stapling is one of the most commonly used methods to stabilize the secondary structure of peptides as a way to provide enhanced functionality [1,2,3]. Molecules 2020, 25, 4667 epoxidation of chalcone catalyzed by a helical peptide-based primary amino catalyst possessing a crosslink between two L-homoserines at the i,i+4 positions (Figure 1) [24,25]. Secondary catalyzed by a helical peptide-based primary amino catalyst possessing a crosslink between two amino catalysts are powerful catalysts with a broad range of applicable reactions [26,27]. Secondary amino catalysts are powerful the peptide hydrocarbon staplings at the i,i+1 and i,i+3 [28,29] positions are rarely examined catalysts with a broad range of applicable reactions [26,27]. Catalysts with stapling at i,i+1 and i,i+3 (This work)
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