Klipkov A. A. Synthesis, chemical and biological properties of 2,3-dihydro-1H-pyrrolizines and 5,6,7,8-tetrahydroindolizines based on α,β-unsaturated fluoroalkyl ketones. – Qualification scientific work on manuscript rights.
Dissertation for Doctor of Philosophy degree by specialty 102 “Chemistry”. National University of ''Kyiv-Mohyla Academy'', Kyiv, 2023.
The thesis is devoted to the development of preparative methods for the synthesis of new polyfluoroalkyl-containing pyrroles, in particular 2,3-dihydro-1H-pyrrolizines and 5,6,7,8-tetrahydroindolizines, based on readily available N-(β-trifluoroacetyl)vinyl (TFAV) derivatives of α-amino acids, as well as research into the possibilities of functionalization and biomedical application of synthesized compounds.
The interaction of N-(β-trifluoroacetyl)vinylproline with a number of dehydrating reagents was investigated and it was found that use of acetic or trifluoroacetic anhydrides leads to selective formation of target 7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolysine. We proposed a mechanism for the formation of trifluoromethyl-containing derivatives of pyrrolizine. The interaction of N-(β-trifluoroacetyl)vinylpipecolic acid with acetic anhydride led to tetrahydroindolizine containing a trifluoroacetyl group and an acetate fragment. The formation of different reaction products under the same conditions can be explained by different conformational behavior of the 5- and 6-membered rings. Finally, the target 1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizine was obtained by heterocyclization of N-(β-trifluoroacetyl)vinylpipecolic acid under the rection with TFAA.
Further, the developed heterocyclization methods were tested on a wider range of starting compounds. Experiments proved that in the case of enaminones containing CF2H-, CF2Cl-, and CF2Br-groups, the target compounds were not obtained by any of the methods. Increasing the length of the polyfluoroalkyl substituent (C2F5, n-C3F7) in the substrate leads to the formation of compounds containing an acetate fragment and a polyfluoroacetyl group in their structure when acetic anhydride was used as a condensing agent. Pyrroles containing polyfluoroalkyl substituents were synthesized by reaction with TFAA. An increase in steric factors is similarly manifested in the case of N-substituted glycines.
The next part of the work was the development of methods for the functionalization of dihydropyrrolizine system. The conducted studies showed that synthesized trifluoromethyl-containing pyrroles can be functionalized at the α-position of the pyrrole fragment using an acylation Friedel-Crafts reaction.
Halogenation of the pyrrole cycle by N-halogenosuccinimides occurs easily at the 5 position of the 7-CF3-dihydropyrrolizine platform at room temperature. Based on observations, α-substituted dihydropyrrolizines were used in the reaction with NBS for preparation of compounds with two functional groups.
Metalation of 5-bromo-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolizine using n-butyllithium was also carried out. The formed organolithium derivative was investigated in reactions with various electrophilic reagents. As a result, dihydropyrrolizines with different functional groups were obtained. In this way, the use of organometallic compounds is a powerful method of modifying the α-position of outlined heterocyclic system.
In the course of selection conditions for the catalytic reduction of the pyrrole cycle, a number of catalysts and the influence of other parameters of the reaction were investigated. 10% Pd/C and acetic acid as solvent was found to be the most efficient system. As a result, diastereomerically pure trifluoroheliotridane with cis-configuration of the chiral centers was obtained for the first time in gram scale. This compound is a fluorine-containing analogue of heliotridane – the parent structure for a number of naturally occuring pyrrolizidine alkaloids.
A set of 13 compounds synthesized in the work was selected for the study of antimicrobial activity. Based on the developed QSAR model, 6 compounds from this set were selected as promising derivatives for in vitro determination of their antimicrobial activity. According to the obtained results, compounds turned out to be effective synthetic antimicrobial agents with a wide spectrum of antimicrobial activity, including multiresistant gram-positive and gram-negative bacterial pathogens.
The in vivo acute toxicity of trifluoromethyl-containing pyrroles was also investigated in the D. magna hydrobiont model. According to the results of these experiments, the compounds belong to the category of moderately and slightly toxic.
Keywords: trifluoromethyl, enones, enaminones, heterocyclization, mechanism, pyrrolizine, indolizine, pyrrole, amino acids, antimicrobial activity.
