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, (1 S ,3 S )-Ac 5 c 3OAll and (1 R ,3 S )-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 (1 S ,3 S )- and (1 R ,3 S )-Ac 5 c 3OAll amino acids showed a right-handed α-helical crystal structure.