Robust trans-amide helical structure of oligomers of bicyclic mimics of β-proline: impact of positional switching of bridgehead substituent on amide cis-trans equilibrium.

Abstract

Because homooligomers of 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acid, a bridged β-proline analogue with a substituent installed at the remote C4-bridgehead position, completely biased the amide cis-trans equilibrium to the cis-amide structure, we expected that introduction of a substituent at the C1-bridgehead position adjacent to the carboxylic acid moiety, rather than the remote C4-bridgehead position, would tip the cis-trans amide equilibrium toward trans-amide structure without the aid of hydrogen bonding. Thus, in this work we established an efficient synthetic route to an optically active bicyclic analogue of 1,1-disubstituted β-proline, bearing a substituent at the C1-bridgehead position. Crystallographic, spectroscopic, and computational studies showed that indeed oligomers of this analogue take a consistent helical structure involving all-trans-amide linkages, independently of the number of residues, from the dimer up to the octamer. Oligomers composed of (R)-β-amino acid units form an extended left-handed helix with about 2.7 residues per turn and an approximately 4.0 Å rise per residue, characterized by complete lack of main-chain hydrogen bonding. This unique helical structure shows some similarity in shape to the trans-amide-based polyproline II (PPII) helix. The present helix was stable in various kinds of solvents such as alcohols. The present work provided a fundamental structural basis for future applications.