Medium ring lactams in molecular recognition

β-Turns are ubiquitous in bioactive conformations of important peptides. We have designed a family of seven-membered lactam dipeptide mimics which are expected to act as conformational constraints in enforcing type Via β-turns in peptide chains. Molecular modelling using Macromodel predicts that both 3(S)-acetylamino-7(S)-carboxy-azepan-2-one N-methyl amide (1, the cis-disubstituted lactam, MM2) and 3(S)-acetylamino-7(R)-carboxy-azepan-2-one N-methyl amide (2a, the trans-disubstituted lactam, MM2 and AMBER) should exhibit features of type VI β-turns. The synthesis and structural analysis of the cis-(1) and trans-disubstituted (2) seven-membered lactam constraints are reported. X-Ray crystallographic analysis and solution NMR measurements offer insight into the preferred conformations of these molecules. Variable temperature NMR data and vapour pressure osmometry of 1 in solution indicate that it exhibits a strong cooperative recognition phenomenon to form a novel dimer, a feature not demonstrated by the trans-isomer 2a, which has a type Via β-turn-like conformation in the solid state. These phenomena can be realistically modelled in molecular dynamics simulations, and demonstrate potential for the design of new materials by self-assembly.