Conformational Analysis and Organocatalytic Activity of Helical Stapled Peptides Containing α-Carbocyclic α,α-Disubstituted α-Amino Acids.

Abstract

Conformational freedom-restricted peptides, such as stapled peptides, play a crucial role in the advancement of functional peptide development. We synthesized stapled octapeptides using α-carbocyclic α,α-disubstituted α-amino acids, particularly 3-allyloxy-1-aminocyclopentane-1-carboxylic acid, as the crosslink motifs. The organocatalytic capabilities of the synthesized stapled peptides were assessed in an asymmetric nucleophilic epoxidation reaction because the catalytic activities are known to be proportional to α-helicity. Despite incorporating side-chain crosslinks, the enantioselectivities of the epoxidation reaction catalyzed by stapled octapeptides were found to be comparable to those obtained using unstapled peptides. Interestingly, the stapled peptides using α-carbocyclic α,α-disubstituted α-amino acids demonstrated higher reactivities and stereoselectivities (up to 99% ee) compared to stapled peptides derived from (S)-α-(4-pentenyl)alanine, a commonly used motif for stapled peptides. These differences could be attributed to the increased α-helicity of the former stapled peptide in contrast to the latter, as evidenced by the X-ray crystallographic structures of their N-tert-butoxycarbonyl derivatives.