The effect of backbone stereochemistry on the folding of acyclic beta(2, 3)-aminoxy peptides

As a new type of foldamer, beta-aminoxy peptides have the ability to adopt novel beta N--O turns or beta N--O helices in solution. Herein, we describe a new subclass of beta-aminoxy peptide, that is, peptides of acyclic beta(2, 3)-aminoxy acids (NH(2)OCHR(1)CHR(2)COOH), in which the presence of two chiral centers provides insight into the effect of backbone stereochemistry on the folding of beta-aminoxy peptides. Acyclic beta(2, 3)-aminoxy peptides with syn and anti configurations have been synthesized and their conformations investigated by NMR, IR, and circular dichroism (CD) spectroscopic, and X-ray crystallographic analysis. The beta N--O turns or beta N--O helices, which feature nine-membered rings with intramolecular hydrogen bonds and have been identified previously in peptides of beta(3)- and beta(2, 2)-aminoxy acids, are also predominantly present in the acyclic beta(2, 3)-aminoxy peptides with a syn configuration and N--O bonds gauche to the C(alpha)--C(beta) bonds in both solution and the solid state. In the acyclic beta(2, 3)-aminoxy peptides with an anti configuration, an extended strand (i.e., non-hydrogen-bonded state) is found in the solid state, and several conformations including non-hydrogen-bonded and intramolecular hydrogen-bonded states are present simultaneously in nonpolar solvents. These results suggest that the backbone stereochemistry does affect the folding of the acyclic beta(2, 3)-aminoxy peptides. Theoretical calculations on the conformations of model acyclic beta(2, 3)-aminoxy peptides with different backbone stereochemistry were also conducted to elucidate structural characteristics. Our present work may provide useful guidelines for the design and construction of new foldamers with predicable structures.