Preferred 3D‐Structure of Peptides Rich in a Severely Conformationally Restricted Cyclopropane Analogue of Phenylalanine

Abstract

Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.

1H‐Azepine‐4‐amino‐4‐carboxylic Acid: A New α,α‐Disubstituted Ornithine Analogue Capable of Inducing Helix Conformations in Short Ala‐Aib Pentapeptides

“…All of the above data suggest that a 3 10 ‐helix construct is present at the C‐termini and that the hydrogen bonds involving NH‐3, NH‐4, NH‐5, and NH‐6 are preserved up to 60 °C 7d. 29…”

“…First, the coupling was attempted by using the already mentioned conditions with the aid of microwave irradiation (55 °C, 400 W, 30 min), but no positive results were obtained. According to a known procedure,7d a mixture of activating reagents (HOAT, 2 equiv; HBTU, 1 equiv) in the presence of DIPEA (4 equiv) was used, but only after 5 days was a trace amount of 11 b obtained. A further attempt was made by converting the dipeptide 10 b into the corresponding more reactive acyl fluoride but, curiously, no reaction occurred.…”

“…Compound 3 was synthesized on a gram scale and orthogonally protected at its two nitrogen atoms, thus enabling its use for the preparation of model peptidomimetics. As azepino derivative 3 is chiral, its preparation represented an added value with respect to Api since different effects on the peptide conformation could be expected depending on the absolute configuration of the starting amino acid 7d…”

Helical screw‐sense preferences of peptides based on chiral, Cα‐tetrasubstituted α‐amino acids

“…A number of X‐ray diffraction structures of di‐, tri‐, and tetrapeptide alkylamides containing ( S,S )‐ or ‐( R,R )‐c 3 diPhe in combination with l ‐Val or l ‐Ala residues have been reported . In these peptides, although the overall backbone conformation is influenced by the chiral sequence of the amino acid building blocks, ( S,S )‐c 3 diPhe is always left‐handed helical.…”

“…In these peptides, although the overall backbone conformation is influenced by the chiral sequence of the amino acid building blocks, ( S,S )‐c 3 diPhe is always left‐handed helical. In addition, a terminally protected, Aib‐based hexapeptide containing two ( S,S )‐c 3 diPhe residues at positions 1 and 4 adopts a left‐handed 3 10 ‐helical conformation in the crystal state …”