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

Organic & Biomolecular Chemistry Pub Date: 2011-03-11 DOI: 10.1039/C0OB01146K

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)-Ac5cdOM] and its enantiomer (R,R)-Ac5cdOM} 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)-Ac5cdOM; 4: (R,R)-Ac5cdOM] and Boc-(L-Leu-L-Leu-dAA)3-OMe [dAA = 5: Aib; 6: Ac5c; 7: (S,S)-Ac5cdOM; 8: (R,R)-Ac5cdOM], 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 Ac5cdOM 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 Ac5cdOM 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)-Ac5cdOM hexapeptide 3 formed a (P) α-helix. In addition, the Ac5c nonapeptide 6 and (R,R)-Ac5cdOM 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 Ac5cdOM residues have a penchant for forming α-helices.

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