In this work we present an easy, one-step synthetic protocol to explore a large chemical space of glutarimide-based cereblon (CRBN) ligands for targeted protein degradation. It is built upon our recently suggested approach to generating structurally diverse series of alpha-substituted glutarimide derivatives through an efficient Rh(II)-catalyzed X-H insertion reaction of 3-diazopiperidine-2,6-dione, with moderate to high yields. In total, 25 glutarimide derivatives incorporating variable side chains were synthesized and evaluated in vitro. All ligands showed a favorable lipophilicity, and several were able to outperform the binding affinity of thalidomide as a reference. In addition, most compounds showed low intrinsic cytotoxicity in myeloma cell lines and human peripheral blood mononuclear cells, and did not recruit canonical neosubstrates. A cellular thermal shift assay further demonstrated that the most potent analogues stabilize CRBN in live cells, confirming their on-target engagement. The development of the series was accompanied by a crystallographic study, which rationalizes the observed improvements in binding affinity and neosubstrate selectivity, and can support further development towards molecular glue activity and PROTACs design.