The synthesis of trifluoromethyl oxetanes using mild Corey-Chaykovsky epoxidation/ring-expansion conditions on trifluoromethyl ketones was developed. In addition, the trifluoromethyl oxetane group was evaluated as a tert-butyl isostere in the γ-secretase modulator (GSM) program. We demonstrated that the trifluoromethyl oxetane-containing GSM has reduced lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analog, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere. We hope this report of facile synthesis and late-stage installation will enable future application of this trifluoromethyl oxetane group in medicinal chemistry.

Trifluoromethyl oxetanes: Synthesis and evaluation as a tert-butyl isostere in the gamma secretase modulator program

255th National Meeting (2018)

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