Відділ 1 - ІБОНХ ім. В. П. Кухаря НАН України

DEPARTMENT OF FINE ORGANIC SYNTHESIS (TOC)

Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine
was founded in 1984.

HEAD OF DEPARTMENT: доктор хімічних наук Герус Ігор Іванович

For a long time the Head of the Department was the academician of the NAS of Ukraine, Professor Valeriy Kuhar.

VP Kuhar was a member of the Supervisory Board of the Ettoire Majorana Scientific Culture Science Center and the World Laboratory (Italy), a member of the EBRD's Chornobyl Shelter Fund (EBRD), a member of the International Chemical Safety Center's Supervisory Board (Poland)

V.P. Kukhar is the author over 600 inventions and scholarly works, including several monographs in international publications

Photo: V.P. Kukhar

MAIN SCIENTIFIC FIELD OF THE DEPARTMENT - Development of methods for the directed synthesis of new organo-fluoro and organophosphorus reagents for the production of biologically active compounds.

It is known that the replacement of individual structural parts of natural compounds with organo-organic fragments leads to impressive results in modulating biological activity.

For example, the introduction of fluorine atoms into the structure of bioactive molecules does not lead to significant changes in the spatial structure of organic molecules because the size of the hydrogen and fluorine atoms is very close. However, the particular electronic properties of fluorine atoms and fluorine-containing groups often lead to fundamental changes in chemical behavior and biological activity. Numerous recent studies show that the deterministic introduction of fluorine atoms into the structure of molecules leads to new effects in the interaction of these compounds with biological targets, they can be perceived as natural substrates and at the same time to reveal fundamentally new functions.

Another promising area of research for biologically active compounds is phosphorus-containing organic substances. The role of phosphates in important biological processes is well known; numerous phosphonates have been found in living organisms - compounds with SR bonds. At the same time, the use of bis-phosphonates as highly active drugs is widely known. Phosphorus compounds are used as pro-drugs for better transport of drugs to a biological target; It is interesting and promising to use in the structures of organophosphorus molecules such fluorine fragments that model the phosphate bond. Therefore, the search for new bioregulators among organophosphorus compounds is rapidly expanding.

RESULTS FOR THE LAST 5 YEARS IN THE DEPARTMENT:

1. New synthetic approaches to fluoroalkyl-containing aromatic compounds have been developed using the Diels-Alder reaction and a wide range of polyfunctional aminobenzoic acid derivatives has been obtained.

2. New difluoro- and hydroxy-methylene-containing eons were synthesized, their physicochemical properties were investigated and their considerable synthetic potential was demonstrated in the synthesis of new potential fluorine-containing bioregulators of heterocyclic and carbocyclic nature.

3. Fluorinated aliphatic and aromatic amino acids in the form of racemates and individual enantiomers have been synthesized. To achieve this goal, methods have been developed for constructing the desired fluorine-containing blocks and introducing them into desired structures, asymmetric synthesis methods using asymmetric induction, or direct introduction of fragments into enantiomerically pure molecules.

4. New synthetic approaches have been developed and the first GORA-derived fluoroalkyl derivatives, analogs of the drug pregabalin, and an initial evaluation of their modulatory effect on neurotransmitter transport in nerve terminals of the brain.

5. The Petasis reaction with the participation of aminophosphonates and aminobisphosphonates was investigated, the main chemical and stereochemical features of this reaction were established. On the basis of the obtained results, an effective method of obtaining C-substituted derivatives of N- (phosphonomethyl) glycine was proposed and its use in the synthesis of highly functional biologically active aminophosphonic acids was demonstrated.

6. A new and effective method of synthesis of trifluoromethyl-containing analogues of thalidomide, a well-known drug, has been developed.

7. Among the synthesized compounds were found to be substances with a pronounced insecticidal, bacterial, immunomodulatory effect with effect on humoral and cellular immunity.

8. A detailed study of the structure of beta-alkoxy and beta-amino-substituted vinyl (polyfluoroalkyl) ketones is carried out by means of IR- and UV spectroscopy.

All studies are based on the widespread use of modern methods, including NMR, GCL, HPLC and IR .

INVENTIVE ACTIVITIES:

Patents:
1. Method of producing synthetic diesel component from vegetable fats
2. Method of obtaining biodiesel fuel by ethanol transesterification of fats
3. Method of purification of petroleum products from sulfur-containing compounds
4. Device for the purification of petroleum products from sulfur-containing compounds.

INTERNATIONAL SCIENTIFIC AND SCIENTIFIC COOPERATION FOR THE LAST 5 YEARS:

1. Investigation of phase transitions of mixtures of enantiomers, in particular, sublimation of mixtures of natural amino acids of the Joint Action Program between Ukraine and France in the field of scientific and technological cooperation Sciences Chimiques de Rennes, Ecole nationale Superieure de Chimie de Rennes 2013-2014

2. New transformations of fluorine-containing ketones with organophosphorus
compounds. DFG, Germany GZ: University of Bremen, Bremen, Germany 2009-2011.

3. New synthetic pathways to polyfluoroalkyl-containing amino- and / or hydroxy acids with potential biological activity. DFG, Germany University of Münster, Münster, Germany 2009-2011.

MOST IMPORTANT PUBLICATIONS FOR THE LAST YEARS

1. Kondratov I., Tolmachova N., Dolovanyuk V., Gerus I., Daniliuc С. and Haufe G. Synthesis of Trifluoromethyl-Containing Polysubstituted Aromatic Compounds by Diels-Alder Reaction of Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-carboxylate. Eur. JOC. 2015б 11, 2482-2491.

2. Romanenko V. D. Kukhar V. P. Progress in the development of pyrophosphate bioisosteres: Synthesis and biomedical potential of 1-fluoro-
and 1,1-difluoromethylene-1,1-bisphosphonates. Curr. Org. Chem . 2014,
18, 1491-1512.

3. Shaitanova E.N., Gerus I.I., Kukhar V.P., Haufe G. Synthesis of enantiomerically pure 4-polyfluoromethyl-4-hydroxy-homoprolines
by intramolecular cyclization of 6-amino-5-polyfluoromethyl-hex-2-enoic
acids Journal of Fluorine Chemistry, 2014, vol. 160, p. 8-11.

4. Kondratov I.S., Tolmachova N.A., Dolovanyuk V.G., Gerus I.I., Bergander K., Daniliuc C.-G., Haufe G. Diels-Alder Reaction of Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-carboxylate with Alkoxyalkenes as an Effective Approach to Trifluoromethyl-Containing 3-Aminobenzoic Acid Derivatives Eur. J. Org. Chem. 2014, vol. 2014, (12), p. 2443-2450.

5. Prokopenko V. Kovalishyn V. Shevchuk M. Kopernyk I. Metelytsia L. Romanenko V. Mogilevich S. Kukhar V. Design and synthesis of new potent inhibitors of farnesyl pyrophosphate synthase. Current Drug Discovery Technologies 2014, 11, 133-144.

6. Acena J. L. Sorochinsky A. E. Soloshonok V. Asymmetric synthesis of alpha-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations Amino Acids, 2014, 46, 2047-2073.

7. Wang J.Sanchez-Rosello M.J. Acena L. del Pozo C. Sorochinsky A. E. Fustero S. Soloshonok V. A. Liu H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001?2011) Chem. Rev. 2014, 114, 2432-2506.

8. Turcheniuk K.V., Kukhar V.P., Roschenthaler G.-V., Aceia J.L., Soloshonok V.A., Sorochinsky A. E. Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids RSC Adv., 2013, 3, 6693-6716.

9. Shevchuk M.V., Kukhar V.P., R?schenthaler G.-V., Bassil B.S., Kawada K., Soloshonok V.A., Sorochinsky A.E. New asymmetric approach to trifluoromethyl isoserines. RSC Adv., 2013, 3, 6479-6484.

10. Bugera M.Ya., Tarasenko K. V., Kukhar V.P., R?schenthaler G.-V., Gerus I.I. Synthesis and Properties of ?-Bromomethyl-substituted Ethoxyvinyl Polyfluoroalkylketones Synthesis. 2013. 45. 3157- 3163.

11. Vdovenko S.I., Gerus I.I., Fedorenko H.A., Kukhar V.P. The conformational analysis of push-pull enaminones using Fourier transform IR and NMR spectroscopy, and quantum chemical calculations. IV. 4-(N,N-dimethylamino)-1,1,1-trifluoro-3-methylbut-3-en-2-one and 4-(N,N-dimethyl-amino)-1,1,1-trifluoropropen-3-en-2-one Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2013. 103, 368-377.

12. Vdovenko S., Gerus I. Fedorenko E. Kukhar V. The conformational analysis of push-pull enaminones using Fourier transform IR and NMR spectroscopy, and quantum chemical calculations. IV. 4-(N,N-dimethylamino)-1,1,1-trifluoro-3-methylbut-3-en-2-one and 4-(N,N-dimethyl-amino)-1,1,1-trifluoropropen-3-en-2-one. Spectrochimica Acta 2012.

13. Gerus, I.I. Mironetz, R. X Kondratov, I. S. Bezdudny, A. V. Dmytriv, Y. V. Shishkin, O. V. Starova, V. S. Zaporozhets, O. A. Tolmachev, A. A. Mykhailiuk, P. K. Reported, but Still Unknown.” A Closer Look into 3,4-Bis- and 3,4,5-Tris(trifluoromethyl)pyrazoles J. Org. Chem., 2012, 77, p. 47-56.

14. Kondratov, I. S. Dolovanyuk, V. G. Tolmachova, N. A. Gerus, I.I. BerganderK. Fr?hlich, R. Haufe, G. Reactions of alkoxyvinylpolyfluoroalkyl
ketones with ethyl isocyanoacetate and its use for the synthesis of new
polyfluoroalkylpyrroles and pyrrolidines Organic & Biomolecular chemistry
2012, 10, 8778-8785.

15. Tarasenko K.V., Manoylenko Olga V., Kukhar V. P., Roschenthaler G., Gerus I.Synthesis of new polyhalogenoalkyl-containing phosphonates with an enaminone core and their use in the preparation of fluorinated heterocycles Tetrahedron Letters, 51, Issue 35, 2010, p. 4623-4626.

16. Sorochinsky A. E., Soloshonok V. A. Asymmetric synthesis of fluorine-containing amines, amino alcohols, – and -amino acids mediated by chiral sulfinyl group. ournal of Fluorine Chemistry, 2010, 131, 127-139.

17. Kukhar V., Romanenko V. Chemistry of aminophosphonic acids and phosphonopeptides Amino Acids, Peptides and Proteins in Organic Synthesis, 2009, vol. 2, p. 191-263.

18. Vdovenko S.I., Gerus I.I., Kukhar V.P. Solvent inluence on the infrared spectra of beta-alkoxyvinyl methyl ketones II. Stretching vibrations and integrated intensities of carbonyl and vinyl bands of (3Z,E)-4-ethoxy-1,1,1-trifluoro-5,5-dimethylhex-3-en-2-one Spectrochimica Acta Part A, 2009, 72, 229-235.

19. Tarasenko K.V., Manoylenko Olga V., Kukhar V. P., Roschenthaler G., Gerus I. Synthesis of new polyhalogenoalkyl-containing phosphonates with an enaminone core and their use in the preparation of fluorinated heterocycles Tetrahedron Letters, 2010, 51, p. 4623-4626.

The staff of the department constantly take part in Ukrainian and international conferences and symposia. The next Symposium on the 21st International Symposium on Fluorine Chemistry & 6th International Symposium on Fluorouse Technologies will be held in Como, Italy on August 23-28, 2015.