E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

We present an E-selective ring-closing metathesis reaction in alpha-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic alpha,alpha-disubstituted alpha-amino acids, (1S,3S)Ac(5)c(3OAll) and (1R,3S)-Ac(5)c(3OAll), provides a high E-selectivity of a <= 59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1-0.5:1 were produced with standard acyclic (S)-(4-pentenyl)alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac(5)c(3OAll) amino acids showed a right-handed alpha-helical crystal structure.

Automated summary

In this study, a selective E-type ring-closing metathesis reaction was discovered in α-helical stapled peptides. By using chiral carbocyclic α,α-disubstituted α-amino acids, a high E-selectivity was achieved, while standard acyclic amino acids resulted in lower selectivity. The stapled octapeptide exhibited a right-handed α-helical crystal structure.