Ring-closing metathesis (RCM) reactions of peptides are powerful tool for stabilizing their secondary structure. However, these methods generally give a mixture of E and Z isomers. In this study, we developed an E-selective ring-closing metathesis reaction on the peptide side-chains based on five-membered cyclic α,α-disubstituted α-amino acids. Chiral five-membered carbocyclic α,α-disubstituted α-amino acids were introduced at the i, i+4 positions of peptides, and the side chains were crosslinked using second generation Grubbs catalyst. The intramolecular RCM reaction using O-allyl L-serine as the cross-linking motif gives a mixture of E and Z isomers (E/Z = 5:1). On the other hand, the RCM reaction proceeded with high E selectivity for the peptides bearing five-membered carbocyclic α,α-disubstituted α-amino acids (E/Z = up to 35:1). In addition, even for short peptides such as hexapeptides and pentapeptides, the RCM reaction also proceeded E-selectively in high yields.

E-selective ring-closing metathesis for i, i+4 stapled peptides using five-membered carbocyclic α,α-disubstituted α-amino acids

ACS Spring Meeting 2021

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