Figure 8.

Key methods to assemble PROTAC libraries using alkyl and ether linkers. A. Nucleophilic aromatic substitution of 32 with linkers carrying an array of functionalities (34–38) was used to build a toolbox of compounds for CRBN PROTAC development (33); B. representative example synthesis of linkers with varying ether combinations; commercially available 39 was sequentially alkylated with 40 and 42. The chloride handle in 43 was subsequently converted to a Cbz-protected amine (45) after further manipulations; C. synthesis of a PROTAC library (47) by alkylation of lenalidomide (11) with various alkyl bromides/iodides (46)