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Here, we report the design, synthesis, and evaluation of fluorinated aminopiperidones as three\u2010dimensional, non\u2010glutarimide thalidomide analogs. By replacing a single glutarimide carbonyl with a stereogenic C*\u2013CF\n                    <jats:sub>3<\/jats:sub>\n                    unit, we accessed a previously underexplored chemical space encompassing all regio\u2010 and diastereomeric variants of 3\u2010 and 5\u2010phthalimido\u20106\u2010trifluoromethyl\u20102\u2010piperidones. Stereocontrolled synthetic routes enabled reliable control over relative configurations, and two\u2010dimensional NMR provided unambiguous structural assignment. Experimental profiling of CF\n                    <jats:sub>3<\/jats:sub>\n                    \u2010piperidones relative to glutarimides revealed improved aqueous solubility despite increased log\n                    <jats:italic>D<\/jats:italic>\n                    and enhanced membrane interaction characteristics, without substantial changes in plasma protein binding, consistent with sp\n                    <jats:sup>3<\/jats:sup>\n                    enrichment and escape\u2010from\u2010flatland principles. To assess whether cereblon recognition is retained after carbonyl\u2010to\u2010C*\u2013CF\n                    <jats:sub>3<\/jats:sub>\n                    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\u2013ligand interactions and unfavorable binding poses following carbonyl\u2010to\u2010C*\u2013CF\n                    <jats:sub>3<\/jats:sub>\n                    substitution. Several CF\n                    <jats:sub>3<\/jats:sub>\n                    \u2010piperidones, particularly tetrafluorophthalimide derivatives, exhibited potent anti\u2010angiogenic activity in vitro and ex vivo, indicating a cereblon\u2010independent mechanism.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70360","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T03:36:47Z","timestamp":1783481807000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fluorinated Aminopiperidones as Non\u2010Glutarimide Thalidomide Analogs: Stereodivergent Synthesis and Validation"],"prefix":"10.1002","volume":"21","author":[{"given":"Bo\u0161tjan","family":"Adamlje","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  Ljubljana 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