Synthesis and Hydrogen Bonding Capabilities of Biphenyl-Based Amino Acids Designed To Nucleate β-Sheet Structure

Abstract

The syntheses of 3‘-(aminoethyl)-2-biphenylpropionic acid (1) and 2-amino-3‘-biphenylcarboxylic acid (2) are described. These residues were designed to nucleate β-sheet structure in aqueous solution when incorporated into small, amphiphilic peptides in place of the backbone of the i + 1 and i + 2 residues of the β-turn. N-Benzyl-3‘-(2-(benzylamido)ethyl)-2-biphenylpropamide (3) and N-benzyl-(2-benzylamido)-3‘-biphenylamide (4) were synthesized and studied as model compounds to investigate the hydrogen-bonding capabilities of residues 1 and 2, respectively. The X-ray crystal structure of 3 indicates that a 13-membered intramolecular hydrogen-bonded ring is formed, while the remaining amide proton and carbonyl are involved in intermolecular hydrogen bonding. Infrared and variable-temperature NMR experiments indicate that, in solution (CH₂Cl₂), 3 exists as an equilibrium mixture of the 13- and the 15-membered intramolecularly hydrogen-bonded conformers with the 15-membered ring conformer being favored. Amide 4 was shown to exist in solution (CH₂Cl₂) as an equilibrium mixture of the 11-membered intramolecular hydrogen-bonded ring and a nonbonded conformation. No contribution from the 9-membered hydrogen-bonded ring conformation was observed. The X-ray crystal structure of 4 indicated the absence of intramolecular hydrogen bonding in the solid state.