Tkachenko A. Fluorinated conformationally restricted natural amino acids analogues as labels for solid state 19F NMR spectroscopy

The thesis is devoted to the synthesis of fluorinated conformationally restricted natural amino acids analogues and its usage as labels for solid state 19F NMR spectroscopy. The first fluorinated derivative of the 2,4-methanoproline was designed and synthesized. The key transformation of five-step synthetic route is photochemical intramolecular 2+2 cycloaddition, in which bicyclic backbone of desired structure is formed. Presents of fluorine atom and two rigid cyclobutane rings in a bicyclic molecule of the obtained compound allows utilizing it as a label for 19F NMR spectroscopy. Two specialized aromatic 19F NMR labels for substitution of phenylalanine and other aromatic amino acids in peptides was designed and synthesized. Structural rigidity, essential for any label in solid state 19F NMR spectroscopy, is provided with cyclobutane rings for both compounds. Obtained phenylalanine analogues have been incorporated in artificial analogs of known membrane active peptides and have been proved to be compatible with typical solid state peptide synthesis protocols and applicable as labels for solid state 19F NMR study of membrane active peptides. The first polar F-label for solid-state 19F NMR spectroscopy - serine and threonine analogue - was designed and synthesized. Synthetic route from known cyclobutane containing ketoester consists of five steps with overall yield 16%. Incorporation of signal trifluoromethyl group is performed by addition of Ruppert-Prakash reagent to carbonyl group. Structural rigidity is provided with cyclobutane ring. For a side-chain OH-group of synthesized serine analogue an acid-base properties was studied in model tripeptide by liquid-state 19F NMR spectroscopy and shown to be close to the corresponding properties of the natural serine and threonine. Obtained amino acid has been incorporated in artificial analog of antimicrobial peptide Temporine A and has been proved to be compatible with typical solid state peptide synthesis protocols and applicable as a label for solid state 19F NMR study of membrane active peptides.