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The trifluoro-tert-butyl group is a structural analogue of the tert-butyl group in which one of the three methyl groups is replaced by a trifluoromethyl group. Because C–F bonds (~1.35 Å) are longer than C–H bonds (~1.09 Å), the CF3 group occupies more space than a methyl group, making the trifluoro-tert-butyl group slightly larger than tert-butyl.
Upon incorporation of fluorine, the CF3 substituent can also serve as a hydrogen-bond acceptor, forming an additional hydrogen bond with nearby residues.
In addition, the CF3 substituent can prevent oxidation of the tert-butyl group, thereby significantly reducing metabolic clearance and improving pharmacokinetic properties. Owing to these combined features, trifluoro-tert-butyl can serve as a metabolically improved alternative to the labile tert-butyl group.

A representative example is alpelisib(NVP-BYL719), a selective PI3Kα inhibitor approved in 2019 in combination with fulvestrant for the treatment of patients with HR-positive, HER2-negative, PIK3Cα-mutated, advanced or metastatic breast cancer who have progressed after endocrine therapy.
In alpelisib, a trifluoro-tert-butyl group replaces the tert-butyl group of the earlier analogue. This replacement enhances PI3Kα inhibitory potency (IC50 from 14 nM to 5 nM) and significantly reduces metabolic clearance (microsomal rat CL from 77 to 29 mL/min/kg; in vivo rat CL from 39 to 10 mL/min/kg), thereby improving the pharmacokinetic profile.

[References]
📰https://doi.org/10.1016/j.bmcl.2013.05.007
📰https://doi.org/10.1021/acs.jmedchem.5c03492

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