You are here

Fluorine-containing amino acids, amines and diazoalkanes: synthesis and using in medicinal chemistry and agrochemistry


Work number - M 41 FILED

Author:

Mykhailiuk P. K.

 

             Recommended by National Taras Shevchenko University of Kyiv. The scientific project consists of 1 monograph, 1 international patents, 36 scientific articles and 10 conference abstracts published over the past 7 years.

             The cycle of work is an attempt to contribute to the development of modern chemistry and fluoroorganic scientific heritage of world famous fluorine chemistry Kyiv school. During the development of synthetic approaches, special attention was paid to the practical component, because the availability and scalability of the method offers hope for its further use in organic synthesis, NMR studies or in creating new drugs for medical and agrochemical industries.
             The results contribute to solving important scientific problems in the field fluoroorganic chemistry, such as creating a perfect 19F-labels to study the structure and mechanisms of bioorganic molecules on the basis of new conformationally restricted fluorine-containing amino acids, amines and diazoalkanes, and the use of these derivatives in organic synthesis to new biologically active compounds for the purpose of medical chemistry and agricultural chemistry.
             For the first time was performed the design and the synthesis of series of fluorine-containing mono- and bicyclic amino acids to replace the residues of alanine, valine, leucine, isoleucine, phenylalanine serine and proline in peptides. Synthesis of these amino acids that are good labels for peptide studies, is an important difficult task that require the subsequent study of the conformational properties of the obtained peptides.
             For the first time it was studied the conformational properties of the membrane-active peptides modified with our synthesized fluorinated amino acids. It was established that the synthesized amino acids were promising 19F NMR labels as 3D-structure of labeled peptides did not change because of the conformationally restricted side chain. The introduction of fluoro-1-amino-4,4-difluorocyclohexane carboxylate did not change the geometry of the molecule, but affected its pKa and lipophilicity.

Effective approaches to the synthesis of a number of fluorine-containing bicyclic amines - unique piperidines, pyrrolidines, azepanes and morpholines, - were developed.  For the first time it was shown that the introduction of the CF3-substituent into CF3-morpholines did not change the geometry morpholine fragment, but reduced its basicity and increased the hydrophobicity of the molecule.

             For the first time it was developed the in situ generation of diverse diazoalkanes followed reaction with alkenes / alkynes is an effective route towards pyrazoles and pyrazolines with different fluorine-containing substituents. The procedures were highly practical because it did not require the isolation of potentially toxic and explosive gaseous diazo intermediates, did not require the use of an inert atmosphere, catalysts or special solvents. The procedure was scalable, allowing to obtain gram quantities of products.
             For the first time it was shown that the generated in situ fluorine-containing diazoalkanes with electron-withdrawing alkenes / alkynes belongs to type I reactions of [3+2]-cycloaddition that accelerated by electron-withdrawing substituents.
             The synthesized new chemical reagents – difluoromethyldiazomethane, and pentafluoroethyldiazomethane - have been used by the well-known in the world agrochemical companies (Bayer, Syngenta) in research aimed at finding new drugs. The resulting reagents are already used by many research groups (Germany, France, Australia) for the study of peptides.
             Results of this research project are summarized in 1 monograph, 1 international patent, 36 scientific papers (all 36 are in foreign journals), 10 theses. The work of the author is cited in 468 scientific articles, h-index = 16.

  The total number of publications of the author: 1 book, 1 international patents, 97 scientific papers (all 97 are in foreign journals), 59 conference abstracts.