Enabling Access to sp 3 ‐Enriched Targeted Protein Degraders via Redox‐Neutral Radical Cross‐Coupling

ABSTRACT Cullin‐RING Ligase 4 Cereblon (CRL4 CRBN )‐mediated targeted protein degradation (TPD) via cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs) or ligand‐directed degraders (LDDs) represents a new modality in modern drug discovery. However, the CRBN‐binding portion of these degraders has been limited to flat, rigid architectures of conventional glutarimide scaffolds. This study presents a modular route to C3(sp 3 )–C(sp 3 ) linked glutarimides via a redox‐neutral cross‐coupling/palladium‐catalyzed hydrogenation sequence. This two‐step protocol is operationally simple, chemoselective, and broadly tolerant of diverse functional groups. It delivers sp 3 ‐rich, three‐dimensional scaffolds that access previously untapped chemical space. The resulting building blocks are ready for immediate use in the CELMoD and LDD arena and provide a versatile platform for next‐generation TPD design. Preliminary studies of BRD4‐targeting LDDs derived from C3(sp 3 )–C(sp 3 ) linked glutarimides demonstrate CRBN‐dependent degradation of BRD4, underscoring their translational potential.