Abstract
Isosteric replacement of functional groups is an emerging strategy for optimizing bioactive molecules in drug discovery. tert-Butyl group is a particularly important moiety, yet its isosteric replacement with 1-trifluoromethyl-cyclobutyl group has been rather neglected. To enable the advance of this molecular fragment in drug discovery programs, we report the synthesis of over 30 small-molecule building blocks featuring the trifluoromethyl-cyclobutyl fragment, achieved by reacting sulfur tetrafluoride with cyclobutylcarboxylic acids on a gram-to-multigram scale. Furthermore, we characterized the structural properties of this group through X-ray analysis, studied its effect on acid-base transitions, and evaluated its Hammett parameters. Finally, we evaluated the replacement of tert-butyl with 1-trifluoromethyl-cyclobutyl in several bioactive compounds that represent commercial drugs and agrochemicals. Our findings indicate that while the trifluoromethyl-cyclobutyl group exhibited slightly larger steric size and moderately increased lipophilicity, it preserved the original mode of bioactivity in the examined cases and, in some cases, enhanced resistance to metabolic clearance.