Chalyk B. Synthesis of 3-(aminoalkyl)functionalized isoxazole derivatives.

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0825U000017

Thesis Registration Form

0825U000017.pdf

Applicant for

Specialization

  • 102 - Хімія

15-05-2023

Specialized Academic Board

47679

Institute of Organic Chemistry NAS of Ukraine

Essay

The thesis is devoted to the synthesis of 3-functionalized isoxazole derivatives as key building blocks for biomedical research. By the reaction of regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides based on N-Boc-amino acids and different types of dipolarophiles: alkenes/alkynes, methylene-active nitriles (acetonitriles with CN, CO2Me, SO2Me groups and heterocyclic substituents in the α-position), "push-pull" enamines and vinylphosphonates, libraries of (poly)functional isoxazoles were obtained as key building blocks for biomedical research. Based on the metal-free single-flask [3+2]-cycloaddition of in situ formed nitrile oxides, an efficient approach was developed for the synthesis of 3-functionalized 5-CF3-, 5-CHF2- and CH2F-isoxazoles containing ester groups, bromine atoms, chloromethyl, aryl substituents and protected amino groups. Through detailed screening (variation of catalyst, hydrogen pressure, temperature, stirring speed, and solvent), optimal conditions for catalytic hydrogenolysis of the isoxazoline N–O bond of sp3-enriched functionalized 3,5-disubstituted-4,5-isoxazolines were found for the scaled-up synthesis of five-, six-, and seven-membered hydroxylactams.

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Research papers

1. Chalyk, B.A; Kandaurova, I. Y.; Hrebeniuk, K. V.; Manoilenko, O. V.; Kulik, I. B.; Iminov, R. T.; Kubyshkin, V.; Tverdokhlebov, A. V.; Ablialimov, O. K.; Mykhailiuk, P. K. A base promoted multigram synthesis of aminoisoxazoles: valuable building blocks for drug discovery and peptidomimetics. RSC Advances. 2016, 6, 25713−25723.

2. Chalyk, B. A.; Hrebeniuk, K. V.; Gavrilenko, K. S.; Shablykin, O. V.; Yanshyna, O. O.; Bash, D.; Mykhailiuk, P. K.; Liashuk, O. S.; Grygorenko, O. O. Synthesis of Bi- and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles. European Journal of Organic Chemistry, 2018, 22, 2753−2761.

3. Chalyk, B. A.; Hrebeniuk, K. V.; Gavrilenko, K. S.; Kulik, I. B.; Rozhenko, A. B.; Volochnyuk, D. M.; Liashuk, O. S.; Grygorenko, O. O. Synthesis of 4-Hetaryl-isoxazoles from Amino Acid-Derived Halogenoximes and Push-Pull Enamines. European Journal of Organic Chemistry, 2018, 40, 5585−5595.

4. Chalyk, B. A.; Sosedko, A. S.; Volochnyuk, D. M.; Tolmachev, A. A.; Gavrilenko, K. S.; Liashuk, O. S.; Grygorenko, O. O. Regioselective synthesis of isoxazole and 1,2,4-oxadiazole-derived phosphonates via [3 + 2] cycloaddition. Organic & Biomolecular Chemistry, 2018, 16, 9152−9164.

5. Chalyk B. A., Hrebeniuk K. V., Fil Y. V., Gavrilenko K. S., Rozhenko A. B., Vashchenko B. V., Borysov O. V., Biitseva A. V., Lebed P. S., Bakanovych I., Moroz Y. S., Grygorenko O. O. Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes. J. Org. Chem. 2019, 84(24), 15877–15899.

6. Chalyk B. A., Khutorianskyi A. V., Vashchenko B. V., Danyleiko K., Grynyova A., Osipova A. O., Kozytskiy A., Syniuchenko D., Tsymbaliuk A., Gavrilenko K. S., Biitseva A. V., Volochnyuk D. M., Komarov I. V., Grygorenko O. O. Reductive Recyclization of sp3-Enriched Functionalized Isoxazolines into α-Hydroxy Lactams. J. Org. Chem. 2022, 87(2), 1001–1018.

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