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

摘要

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 ? 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.