Conformational analysis of peptides and pseudopeptides incorporating an endo-(2S,3R)-norborn-5-ene residue as a turn inducer

The synthesis of pseudopeptides 1-3 and peptide 4 were reported in the accompanying article. X-ray analysis of pseudopeptide 1 showed it to adopt a solid state conformation in which the Pro-Phe-Phe chain formed two consecutive beta-turns, stabilized by hydrogen bonding between the Phe NH's and the norbornene carbonyls. However, NMR, IR, and CD studies showed that in CDCl3, CH2Cl2, and CH3CN solution, pseudopeptide 1 does not adopt a preferred conformation. A longer pseudopeptide 2 was found to exist ill two different conformations in CDCl3 solution. The major conformer adopts a structure in which both tripeptide chains form a single beta-turn which is stabilized by the formation of a hydrogen bond between the C-terminal amino acid NH and one of the norbornene carbonyls. In the minor conformer, However, the Pro-Phe-Phe chain forms two beta-turns, analogous to the X-ray structure of pseudopeptide 1. The introduction of a urea unit into one of the peptide chains, as in pseudopeptide 3, offsets the atom positions so as to allow interchain hydrogen bonding, and the (3)J(alpha-CH-NH) coupling constants and NOE's suggest that in CDCl3 pseudopeptide 3 adopts a parallel beta-sheet conformation. The parallel beta-sheet is stabilized by the formation of two intramolecular hydrogen bonds involving the NH's of the Ala and Val residues. Finally, peptide 4, which incorporates a conformationally constrained beta-amino acid, was determined by NMR techniques to form an antiparallel beta-sheet (also referred to as a beta-ladder or beta-hairpin). A series of model peptides lacking the norbornene unit were also prepared, and in each case NMR and IR techniques showed that the model peptides did not form well defined conformations containing intramolecular hydrogen bonds.