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Synthesis and study of optically active oxindoles


Author: Bilan Dmitri
Degree:doctor of chemistry
Speciality: 02.00.03 - Organic chemistry
Year:2022
Scientific adviser: Fliur Macaev
doctor habilitat, professor, Institute of Chemistry of the ASM
Institution: Institute of Chemistry of the ASM

Status

The thesis was presented on the 21 January, 2022 at the meeting of the Scientific Council and now it is under consideration of the National Council.

Abstract

Adobe PDF document1.33 Mb / in romanian
Adobe PDF document1.31 Mb / in english
Adobe PDF document1.30 Mb / in russian

Thesis

CZU 547.5 547.7/.8 547.91 544.12 544.164/165

Adobe PDF document 5.41 Mb / in romanian
139 pages


Keywords

oxindole, isatin, chiral substance, cycloaddition, asymmetric synthesis

Summary

ilan Dmitri Iaroslav, “Synthesis and study of optically active oxindoles”. Dissertation for the degree of Doctor of Chemical Sciences. Chisinau, Republic of Moldova, 2022. Dissertation contents: the thesis includes an introduction, 3 chapters, general conclusions and recommendations, a list of references of 144 titles, 108 pages of the main text, 76 figures, 3 tables. The results are published in 21 scientific papers. Keywords: oxindole, isatin, chiral substance, cycloaddition, asymmetric synthesis. The goal of the scientific work: investigation of the routes for selective synthesis of optically active substituted oxindoles on the basis of isatins, investigation of their structure and properties. The research objectives: the elaboration of simple and effective synthetic schemes for obtaining the new substituted oxindoles starting from isatins; study of the regularities of cross-aldol reaction by using chiral catalysts; exploration of the synthetic routes towards the optically active N-substituted isatins; investigation of the reactions of obtaining spirooxindoles from isatin, natural amino acids and chalcones; evaluation of the “structure-bioactivity” relationship for a number of the synthesized substituted oxindoles based on the obtained data of bioassay. The novelty and the scientific originality of the work consists in the development of selective routes for the synthesis of previously unknown compounds belonging to the oxindole series, four of them being characterized by X-ray structural analysis, as well as study of their properties; the possibility of obtaining the potentially bioactive N-glycosylated isatins and spirooxindoles has been presented; the synthetic routes towards a series of new chiral hybrid molecules containing the pyrrolizidine fragment, found in alkaloids, have been investigated; a method was developed for the preparation of symmetrical and unsymmetrical derivatives of natural convolutamidine A and analogs, in which the 3-hydroxy-2-oxindole fragments are linked through an 2-oxopropyl linker. The solved scientific problem consists in the determination of the optimal conditions for the synthesis of heterocyclic compounds of the oxindole series potentially endowed with biological activity and investigation of the "structure-bioactivity” relationship, as well. The optimal conditions for the synthesis of bis-adducts of isatins with acetone have been established. For the first time, a highly stereoselective method for the preparation of (S)-3-hydroxy-3-((R)-2-oxocyclohexyl) indolin-2-one has been proposed. Theoretical significance of the dissertation. The perspective of using a derivative of the natural diterpenoid sclareol and the cyclopentyl ester of L-leucine for the construction of an optically active polyfunctionalized derivative of oxindole containing the pyrrole moiety, has been illustrated. The features have been revealed, regarding the α-aminoalcohols- catalyzed aldol condensation reaction of isatins with acetone. It was found, that the stereoselectivity of the aldol condensation of indolinedione with cyclic ketones is influenced by the nature of the solvent and catalyst. Applicative value of the dissertation: The developed methods formed the basis for the selective synthesis of a series of heterocyclic compounds of oxindole series. The analysis of the “structure-bioactivity” relationship revealed the cytotoxicity of some compounds against the T-cell leukaemia MT-4, and fungicidal and bactericidal activity too, thus being of practical interest, including also photodynamic therapy. Implementation of the scientific results: The patented method of diastereo- and enantioselective construction of optically active oxindoles has been applied in the scientific research activity of Laboratory of Organic Synthesis of the Institute of Chemistry. Data on the cytotoxicity pointed out the promising substances for further in-depth research.