An improved synthesis of 3,4-(aminomethano)proline and its incorporation into small oligopeptides

Starting from the readily available Garner aldehyde, a new synthesis of diastereomerically and enantiomerically pure 3,4-(aminomethano)prolinol (2R,l'S,3S,4S)-17 has been developed using simple and easily scalable transformations. The protected diamino alcohol (2R,l'S,3S,4S)-17 has been shown to be an appropriate compound for the exchange of protecting groups. Final Jones oxidation furnished the correspondingly protected diamino acids in high yields. The newly synthesized Fmoc/Boc-protected 3,4-(aminomethano)proline (Amp). derivatives, which are proline mimics as well as bicyclic gamma-amino acids, depending on the orthogonal protecting group pattern, were employed for solid-phase peptide synthesis with the Fmoc strategy. Thus, the features of Amp as a gamma-amino acid residue (gamma-Amp) were investigated in the preparation of alternating alpha/gamma-amino acid sequences. The obtained highly homogeneous products were characterized by circular dichroism spectroscopy. The fact that the dichroic properties of the alpha/gamma-oligopeptides were independent from the solvent used (water or methanol) suggests the presence of a preferred conformation. These results are encouraging for the development of foldamers based on gamma-Amp units.