We are currently interested in the synthesis and evaluation of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for linear and cyclic peptidomimetics (Chem. Eur. J. 2014, 20, 11187; Bioorg. Med. Chem. 2016, 24, 703; Org. Biomol. Chem. 2017, 15, 6826). A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids have been prepared via the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived enol phosphates, followed by an OH-directed cyclopropanation. By this approach N-Boc, N-Cbz and N-CO2Me protected cyclopropane pipecolic acids bearing one or two hydroxy groups at position 4 and/or 5 (both cis and trans), or an amino group at position 4 or 5 were prepared in good yields. One of these CPA was successfully introduced into a linear peptide sequence to study the cis/trans isomerism about the pipecolic acid peptide bond. Two CPAs with cis relative stereochemistry between the carboxylic group and an amino functionality at position 4 or 5 (one example in figure below) proved instead suitable to prepare a cyclic peptidomimetics bearing the RGD-sequence, which displayed nanomolar activity as ligands of both the alphavbeta3 integrin expressed in M21 human melanoma cells and alpha5beta1 expressed in erythroleukemia K562 cells. Our CPAs appear thus suitable for the generation of novel peptidomimetics for drug discovery.




Currently, we are investigating also 5-amino- and 4-aminopipecolic acids as conformationally constrained amino acids for peptidomimetics. The RGD sequence has been grefted onto one of these two compounds to get a potent (nM) antagonist of the isolate alphavbeta3 integrin receptor (see: Org. Biomol. Chem. 2018, 16, 3402).