Fluorinated Aminopiperidones as Non-Glutarimide Thalidomide Analogs: Stereodivergent Synthesis and Validation.

The glutarimide fragment is a key pharmacophore in cereblon-binding immunomodulatory drugs and proteolysis-targeting chimeras, yet exploration of non-glutarimide scaffolds remains limited. Here, we report the design, synthesis, and evaluation of fluorinated aminopiperidones as three-dimensional, non-glutarimide thalidomide analogs. By replacing a single glutarimide carbonyl with a stereogenic C*-CF3 unit, we accessed a previously underexplored chemical space encompassing all regio- and diastereomeric variants of 3- and 5-phthalimido-6-trifluoromethyl-2-piperidones. Stereocontrolled synthetic routes enabled reliable control over relative configurations, and two-dimensional NMR provided unambiguous structural assignment. Experimental profiling of CF3-piperidones relative to glutarimides revealed improved aqueous solubility despite increased logD and enhanced membrane interaction characteristics, without substantial changes in plasma protein binding, consistent with sp3 enrichment and escape-from-flatland principles. To assess whether cereblon recognition is retained after carbonyl-to-C*-CF3 replacement, the compounds were evaluated by microscale thermophoresis. No measurable cereblon binding was detected for the fluorinated aminopiperidones. Docking studies, performed to rationalize this lack of affinity, suggested disruption of key cereblon-ligand interactions and unfavorable binding poses following carbonyl-to-C*-CF3 substitution. Several CF3-piperidones, particularly tetrafluorophthalimide derivatives, exhibited potent anti-angiogenic activity in vitro and ex vivo, indicating a cereblon-independent mechanism.