Ethers are a ubiquitous functional group in natural products and drug compounds due to their high stability and mild polarity. However, robust synthetic methods to access ether functionalities with wide functional group tolerance remain scarce. Herein, a method to synthesize dialkyl ethers from aliphatic diols under mild conditions is disclosed, utilizing N-heterocyclic carbene reagents to generate alkyl radicals from alcohols and copper catalysis for C O bond formation. Studies were conducted on the mechanism of this reaction that indicate a triplet sensitization cycle is operative, and a preliminary isolated scope is presented.

Immunomodulatory drugs (IMiDs), including thalidomide, pomalidomide, and lenalidomide, are essential therapeutics for multiple myeloma (MM) throughout the course of treatment. However, most patients with MM eventually develop IMiD resistance and relapsed/refractory MM. Although IMiDs are known to target Cereblon (CRBN), an E3 ubiquitin ligase substrate receptor, and induce neo-substrate degradation of critical MM proteins, the mechanisms of resistance development and IMiD action are not fully understood. Here, novel endogenous interactors of CRBN identified via the µMap proximity labeling platform reveal a novel mechanism of action of IMiDs in inhibiting native CRBN co-chaperone function with heat shock proteins (HSPs). Independently of induced neo-substrate degradation, IMiDs destabilize CRBN interactors in lenalidomide-sensitive MM lines and increase apoptotic markers. In contrast, CRBN’s stabilization of proteins and nascent protein synthesis is maintained in lenalidomide-resistant MM lines, which attenuate the IMiD-mediated destabilization effect by upregulating critical HSPs. Combination treatment with HSP inhibitors and IMiDs can leverage this mechanism to sensitize IMiD-resistant MM cells to IMiD treatment. These data establish a novel mechanism of action and nominate native CRBN interactors and chaperone function as therapeutic targets for next-generation MM therapeutics.