An Improved Synthesis of 3,4-(Aminomethano)proline and Its Incorporation into Small Oligopeptides

• Published in: European Journal of Organic Chemistry Vol. 2006; no. 19; pp. 4440 - 4450
• Main Authors: Brackmann, Farina, Colombo, Noemi, Cabrele, Chiara, de Meijere, Armin
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.10.2006; WILEY‐VCH Verlag; Wiley
• Subjects: Amino acids; Chemistry; Chemistry, Organic; Cyclopropanes; Oligopeptides; Physical Sciences; Science & Technology; Small ring systems; HELICAL CONFORMATIONS; PHASE SYNTHESIS; L-PROLINE; oligopeptides; amino acids; cyclopropanes; SHEET SECONDARY STRUCTURE; BETA-PEPTIDES; OLIGOMERS; small ring systems; AMINO-ACIDS; GAMMA-PEPTIDES; FOLDAMERS; SHORT ALPHA/BETA-PEPTIDES
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200600404

Starting from the readily available Garner aldehyde, a new synthesis of diastereomerically and enantiomerically pure 3,4‐(aminomethano)prolinol (2R,1′S,3S,4S)‐17 has been developed using simple and easily scalable transformations. The protected diamino alcohol (2R,1′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 γ‐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 γ‐amino acid residue (γ‐Amp) were investigated in the preparation of alternating α/γ‐amino acid sequences. The obtained highly homogeneous products were characterized by circular dichroism spectroscopy. The fact that the dichroic properties of the α/γ‐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 γ‐Amp units. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)