Stereospecific Synthesis of Conformationally Constrained γ-Amino Acids: New Foldamer Building Blocks That Support Helical Secondary Structure

A highly stereoselective synthesis of novel cyclically constrained gamma-amino acid residues is presented. The key step involves organocatalytic Michael addition of an aldehyde to 1-nitrocyclohexene. After aldehyde reduction, this approach provides optically active beta-substituted delta-nitro alcohols (96-99% ee), which can be converted to gamma-amino acid residues with a variety of substituents at the alpha position. We have used these new building blocks to prepare alpha/gamma-peptide foldamers that adopt a specific helical conformation in solution and in the solid state.