A Facile Protocol for C(sp²)-C(sp³) Bond Formation Reactions Toward Functionalized E3 Ligase Ligands

A straightforward method for creating C(sp²)-C(sp³) bonds is employed to develop novel cereblon (CRBN) E3 ligase ligands, essential for targeted protein degradation (TPD) applications. While most prior studies focus on biological activities, this work explores how the linker attachment and bond types affect physicochemical stability, binding affinity, and degrading performance. Utilizing N-hydroxyphthalimide (NHP) esters and aryl bromides, a resilient decarboxylative cross-coupling technique that broadens the available chemical space beyond traditional C(sp²)-N connections is developed. Several well-established and underexplored CRBN binders and their derivatives are synthesized and studied. Binding affinity, aqueous solubility, stability in microsomes, and degradation of typical CRBN ligand off-targets are then investigated. Selected compounds are transformed into GSPT1-targeting molecular glue degraders or BRD4-targeting proteolysis-targeting chimeras (PROTACs). Benzamide-based degraders obtained using the new method have a very high ability to break down BRD4. This research shows that C(sp²)-C(sp³) connections open up new ways to fine-tune PROTAC characteristics, which unlock degrader chemotypes that were not accessible before. The results demonstrate the importance of synthetic innovation in developing ligands for TPD applications.