Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer

Abstract

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac₅c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac₅c^dOM] and its enantiomer (R,R)-Ac₅c^dOM} were introduced into L-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)₂-OMe [dAA = 1: Aib; 2: Ac₅c; 3: (S,S)-Ac₅c^dOM; 4: (R,R)-Ac₅c^dOM] and Boc-(L-Leu-L-Leu-dAA)₃-OMe [dAA = 5: Aib; 6: Ac₅c; 7: (S,S)-Ac₅c^dOM; 8: (R,R)-Ac₅c^dOM], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac₅c hexapeptide 2 formed right-handed (P) 3₁₀-helices, while Ac₅c^dOM hexapeptides 3 and 4 formed a mixture of (P) 3₁₀- and α-helices. The Aib nonapeptide 5 formed a (P) 3₁₀-helix, the Ac₅c nonapeptide 6 formed a mixture of (P) 3₁₀- and α-helices, and the Ac₅c^dOM nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3₁₀-helix, while (S,S)-Ac₅c^dOM hexapeptide 3 formed a (P) α-helix. In addition, the Ac₅c nonapeptide 6 and (R,R)-Ac₅c^dOM nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac₅c residues have the propensity to form 3₁₀-helices in short peptides, whereas the chiral Ac₅c^dOM residues have a penchant for forming α-helices.