Organocatalytic Access to a <i>cis</i>-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide

Abstract

In this study, we have developed a highly enantioselective organocatalytic route to the (1<i>S</i>,2<i>R</i>)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a <i>cis</i>-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the <i>cis</i>-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding <i>trans</i>-system can be fulfilled by several competing helical structures.