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 α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac₅c^3OAll and (1R,3S)-Ac₅c^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)-Ac₅c^3OAll amino acids showed a right-handed α-helical crystal structure.