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

Four types of alpha,alpha-disubstituted amino acids {i.e., alpha-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(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: Ac(5)c; 3: (S, S)-Ac(5)c(dOM); 4: (R, R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S, S)-Ac(5)c(dOM); 8: (R, R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and alpha-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and alpha-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) alpha-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S, S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) alpha-helix. In addition, the Ac(5)c nonapeptide 6 and (R, R)-Ac(5)c(dOM) nonapeptide 8 formed (P) alpha-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming alpha-helices.