Mixed Oligoureas Based on Constrained Bicyclic and Acyclic β-Amino Acids Derivatives: On the Significance of the Subunit Configuration for Folding

Source: Chemistry – A European Journal, 2013, Volume: 19, Issue: 50, Pages: 16963-16971,  DOI: 10.1002/chem.201302829

C. Andre, B. Legrand, L. Moulat, E. Wenger, C. Didierjean, E. Aubert, M. Averlant-Petit, J. Martinez, M. Amblard, M. Calmes


The combination of a nonfunctionalized constrained bicyclo[2.2.2]octane motif along with urea linkages gave a highly rigid 2.512/14 helical system both in soln. and the solid state.  The authors aimed at developing stable and functionalized systems as promising materials for biol. applications in studying the impact of this constrained motif and its configuration on homo and heterochiral mixed-oligourea helix formation.  Di-, tetra-, hexa-, and octa-oligoureas alternating the highly constrained bicyclic motif of (R) or (S) configuration with acyclic (S)-β3-amino acid derivs. were constructed.  CD, NMR expts., and the x-ray crystal structure of the octamer unequivocally proved that the alternating heterochiral R/S sequences form a stable left-handed 2.5-helix in contrast to the mixed (S/S)-oligoureas, which did not adopt any defined secondary structure.  The (-)-synclinal conformation around the Cα[n.63743]Cβ bond of the acyclic residues, although sterically less favorable than the (+)-synclinal conformation, was imposed by the (R)-bicyclic amino carbamoyl (BAC) residue.  This highlighted the strong ability of the BAC residue to drive helical folding in heterochiral compds.  The role of the stereochem. of the BAC unit was assessed and a model was proposed to explain the misfolding of the S/S sequences.