Chiral Propargylamines - Versatile Building Blocks for Peptidomimetics and Foldamers

• Applicant: Professor Dr. Norbert Sewald
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233267300

The proposed project is aiming at the synthesis and structural analysis of new types of peptidomimetics. The stereoselective synthesis of propargylamines as amino acid analogs and their application as versatile building blocks for peptidomimetics will be a key issue. Formally, the carboxy group of an amino acid is replaced by a terminal alkyne in such a building block. The target enantiomerically pure terminal alkynes will be used in copper-catalyzed azide-alkyne cycloadditions (CuAAC) or in the ruthenium-catalyzed correlate (RuAAC) to provide peptide analogs where the peptide bond is replaced by a triazole moiety. Such 1,4- or 1,5-disubstituted 1,2,3-triazoles are considered substitutes of trans- or cis-configured peptide bonds. Special emphasis will initially be placed on derivatives with substituents that resemble the side chains of proteinogenic amino acids. However, one of the strengths of the proposed approach is that it does not rely on the chiral pool like currently employed methods. Along this line, a broad scope of homo-oligomers of triazoles, the so-called triazolamers, formed by CuAAC or RuAAC will become accessible. Above all, triazolamer-peptide hybrids (oligomers composed of alternating 1,4- or 1,5-disubstituted triazole units and amide bonds) will be obtained as promising peptidomimetics. In addition, the terminal alkyne moiety of the key compounds will be coupled to aryl or heteroaryl halides according to Sonogashira to provide peptidomimetic building blocks and even foldamers by solid phase synthesis. The solution structures of the oligomers will be investigated by NMR in combination with MD calculations. With this information, first principles for the quick structural analysis of such foldamers with CD spectroscopy and for the design of secondary structure mimetics will be established. Perspectively, versatile peptidomimetics will then be designed with the different types of foldamers in order to bind proteins and inhibit protein-protein interaction.

• DFG Programme: Research Grants