Yarmolchuk V. Synthesis of functionalized pyrrolidines by the reaction of 1,3- [3+2]-cycloaddition of an azomethine ylide.

Українська версія

Thesis for the degree of Candidate of Sciences (CSc)

State registration number

0419U000690

Applicant for

Specialization

  • 02.00.03 - Органічна хімія

19-02-2019

Specialized Academic Board

Д 26.001.25

Taras Shevchenko National University of Kyiv

Essay

Pyrrolidine is one of the most frequently used aliphatic amines in organic chemistry. This residue can be found in many bioactive compounds including nine FDA-approved drugs. It is not surprising therefore that substituted pyrrolidine analogues are valuable building blocks that are used in both drug discovery and agrochemistry projects. On the other hand, practical application of building blocks in pharmaceutical and agrochemical industry strongly depends not only on their conceptual attractiveness, but also on their chemical availability. Therefore, elaboration of short and high-yielding synthetic approaches to pyrrolidine analogues is important. For this purpose, new pyrrolidine derivatives (β-prolines), including those containing chiral centers, have been synthesized. The beneficial effects of fluorine as a substituent in organic compounds have stimulated intense research in organofluorine chemistry. The incorporation of fluorine, trifluoromethyl groups, or other fluorinated fragments into organic molecules can significantly change their physicochemical and biological properties. In particular, the trifluoromethyl substituent effectively influences the pKa of the neighboring functional groups, lipophilicity, solubility, conformational preferences, and hydrolytic and metabolic stabilities. Therefore, the trifluoromethyl group is widespread in bioactive compounds. Combination of the principles described above leads to conceptually attractive β-trifluoromethyl-substituted pyrrolidines. A practical synthetic approach to the construction of a library of three isomeric/homologous β-trifluoromethyl-substituted pyrrolidines is disclosed. All products were prepared in multigram quantities from a common precursor. The key synthetic step was a [3+2]-cycloaddition reaction. The influence of the trifluoro-methyl group on the physicochemical characteristics of the pyrrolidine fragment was studied. From the obtained series of isomeric β-trifluoromethyl substituted pyrrolidines it was established that the introduction of the trifluoromethyl substituent into the pyrrolidine fragment had a significant effect on the pKa, logD and metabolic stability of the synthesized compounds. We believe that β-trifluoro-methyl-substituted pyrrolidines will find applications in drug discovery and in agrochemistry as valuable building blocks, and in mechanistic studies as 19F NMR probes.

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