Conformation of dehydropeptides: synthesis and solution structure of model peptides containing (E) and (Z) dehydroaminobu^tyric acid residues

Abstract

Six model dipeptide methyl amides containing dehydroaminobutyric acid (Δ Abu) of the type Boc-X-δ^zAbu-NHCH₃ and Box-X-δ^ε Abu-NHCH₃, X = Ala, Val, Phe (Boc = tert-butoxycarbonyl), have been synthesized and their solution conformations explored using 300 MHz ¹H NMR and IR spectroscopy. Studies based on delineation of intramolecularly hydrogen bonded NH groups in CDCl₃ and (CD₃)₂SO revealed that none of the NH groups is appreciably solvent shielded. Difference NOE (Nuclear Overhauser Effect) studies have also failed to detect the presence of any discernible turn structure in these peptides. These studies indicate that the conformational preferences of peptides containing, α, β-dehydroaminobutyric acid are different from those of Δ^ZPhe and Δ^ZLeu. It appears that steric interactions due to the β-substituent in the dehydroamino acid moiety play an important role. Unlike Δ^ZPhe and Δ^ZLeu, which have relatively large β-substituents, phenyl and isopropyl, respectively, and stabilize a β-turn, the β-methyl group of Δ^ZAbu or Δ^ε Abu is readily accommodated in extended conformation. Clearly, the size of β-substituent in dehydroamino acid crucially influences the conformational preferences. Thus, it may be possible to use different dehydroamino acids to introduce variable but definite constraints in synthetic peptides.