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Updated: Jun 6, 2025
07:50
Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides
Published on: May 26, 2019
9.2K
CF3-Cyclobutanes: Synthesis, Properties, and Evaluation as a Unique tert-Butyl Group Analogue
Volodymyr Ahunovych1,2, Anton A Klipkov1,2, Maksym Bugera1,2
1Enamine Ltd, Winston Churchill st. 78, 02094 Kyiv, Ukraine.
JACS Au
|November 29, 2024
Summary
Researchers developed novel trifluoromethyl-cyclobutyl building blocks as a tert-butyl isostere for drug discovery. This new group maintains bioactivity and can improve metabolic stability in drugs and agrochemicals.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Drug Discovery
Background:
- Isosteric replacement is key for optimizing bioactive molecules.
- The tert-butyl group is crucial, but its isosteric replacement with 1-trifluoromethyl-cyclobutyl is underexplored.
Purpose of the Study:
- To synthesize novel 1-trifluoromethyl-cyclobutyl building blocks.
- To characterize the properties of this group and its impact on bioactivity.
Main Methods:
- Synthesis of over 30 building blocks using sulfur tetrafluoride and cyclobutylcarboxylic acids.
- Structural characterization via X-ray analysis.
- Evaluation of acid-base properties and Hammett parameters.
Main Results:
- Successful gram-to-multigram scale synthesis of trifluoromethyl-cyclobutyl compounds.
- The group shows slightly increased steric bulk and lipophilicity compared to tert-butyl.
- Bioactivity was preserved, and metabolic clearance resistance was enhanced in some cases.
Conclusions:
- The 1-trifluoromethyl-cyclobutyl group is a viable and potentially advantageous isosteric replacement for tert-butyl.
- This fragment can be utilized in drug discovery and agrochemical development to optimize molecular properties.
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