Stabilization of a cis amide bond in a host-guest complex

Macrobicycle 12 has been synthesized and its binding properties with a range of N-acetyl amino acid carboxylates (as tetrabutylammonium salts) have been studied. While the binding results showed little selectivity for the various substrates investigated, detailed NMR studies have revealed that D-amino acid substrates bind predominantly on the outside of the macrobicycle cavity by a strong carboxylate-thiourea interaction, whereas L-amino acid substrates bind predominantly on the inside of the cavity also establishing a strong carboxylate-thiourea interaction but with the acetyl amide in a cis configuration. Molecular modeling studies suggest that the energetic penalty associated with adopting a cis amide configuration in the host-guest complex is compensated by intermolecular hydrogen bonds between the cis amide and the rim of the macrobicycle.