Our attention turned to the incorporation of additional linking groups and click handles to allow potential applications as di-and trifunctional linking reagents considering the azetidine N-vector. From phenol 148 alkylation with propargyl bromide followed by conversion to the ASF gave trifunctional reagent 150. This reagent again performed in the deFS reaction with morpholine (151) as well as with a derivative of thymidine (154). Next, we targeted the installation of a click handle through the azetidine nitrogen atom. From NH azetidine 145, reaction with propargyl chloroformate formed the propargyl carbamate, which was converted to ASF 152. The deFS reactivity was similarly maintained in the reaction with morpholine to generate an amino-azetidine bearing additional N-functionality (153). Targeted protein degradation is a burgeoning field in drug discovery, involving the use of bifunctional small molecules to promote ubiquitination of a protein of interest by an E3 ligase and so initiate subsequent proteasomal degradation. The glutarimide scaffold is effective in binding the cereblon E3 ligase and is found in the most clinically successful degraders thalomid (thaliomide) and revlimid (lenalidomide) and pomalyst (pomalidomide). Proteolysistargeting chimeras (PROTACs) offer exciting potential as new modalities in drug discovery and typically consist of an inhibitor, a linker and an E3 ligase binder. Linker design is itself crucial both to efficacy as well as physicochemical properties of the PROTAC compounds. We envisaged that the use of functionalized OSF and ASF reagents would allow the introduction of cereblon-binding motifs (CBM) and provide new linker designs that may offer potentially advantageous physicochemical or solubility properties. The inclusion of oxetanes or azetidine derivatives would also provide notably different conformations in comparison to amide, ether, or amine links, and hence how the binding elements are displayed. Moreover, the direct modification of lenalidomide or pomalidomide as small molecule derivatives can have a significant effect on degradation potency and profiles, offering exciting new opportunities for drug discovery as molecular glues (eg 155, Scheme 7a). 46 Golcadomide is a pomalidomide-derived molecular glue degrader from Calgene/Bristol-Myers Squibb currently entering phase III clinical trials for large b-cell lymphoma (NCT06356129). 47 Hence there is significant interest in the generation of new cereblon-binding derivatives.