New synthetic pathways to polyfluoroalkyl-containing amino- and hydroxy acids with potential biological activity

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This one-year project is designed to finalize the long-lasting successful collaboration of my group with the group of Igor I. Gerus and Ivan S. Kondratov from the Academy of Sciences of Ukraine in Kiev. The project focuses on the development of new fluorinated amino- and hydroxy acids as potential bioisosteres of natural amino acids and on the investigation of the influence of fluorinated groups on the behavior of such molecules. The introduction of fluorine or polyfluoroalkyl groups into bio-relevant organic molecules is an efficient method for the specific modification of important properties such as dipole moment, basicity/acidity, lipophilicity, and hence of the chemical reactivity and biological activity. By way of example, many fluorine-containing amino acids were synthesized during past years and some of them have attracted particular interest owing to their potential medicinal utility as reversible or suicide inhibitors of certain enzymes, as convenient 19F NMR probes for molecular structure investigations and as building blocks for peptide synthesis. In the first funding period we investigated (i) Diels-Alder reactions of trifluoromethylated pyrones with different dienophiles in order to synthesize new trifluoromethyl containing aromatic amino acids and (ii) the catalytic hydrogenation of 2-amino-5-trifluoromethylpyrones as the basis for the preparation of new fluorinated amino- and hydroxy acids. Continuing our investigations in this field, we will develop stereoselective pathways towards 5-polyfluoroalkyl proline analogs to be used as sterically fixed peptide analogs. Another goal is the preparation and investigation of polyfunctional fluorinated building blocks, which can be applied for the synthesis of different analogs of proline, glutamine, ornithine, etc. bearing fluorine atoms or fluorinated groups in strategic positions. We are also going to finalize our studies in the field of fluorinated GABA analogs of biological interest. Finally we will prepare and investigate trifluoromethoxy containing amino acids, which are scantily explored but are expected to be of interest for bioorganic chemistry, particularly for peptide modeling due to its extremely lipophilic character.