Enabling Access to sp3-Enriched Targeted Protein Degraders via Redox-Neutral Radical Cross-Coupling

Cullin-RING Ligase 4 Cereblon (CRL4 CRBN )-mediated targeted protein degradation (TPD) via cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs TM ) 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 TM 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.