Diversity Synthesis Using Glutarimides as Rhodium Carbene Precursors in Enantioselective C–H Functionalization and Cyclopropanation

Abstract

Cereblon E3 ligase modulatory drugs (CELMoDs) can be used to target proteins and mark them for proteasomal degradation by recruiting them to cereblon (CRBN), the substrate receptor of the CRL4^CRBN E3 ubiquitin ligase complex. Modifications to the stereochemistry and regiochemistry of distal functionality on CELMoDs have been shown to have large effects on degradation activity and selectivity; however, methods allowing the rapid and selective introduction of enantioenriched moieties are rare. Herein, we report that classical CRBN-binding glutarimide cores can be successfully derivatized to aryl diazoacetates. These diazo derivatives, when in the presence of a dirhodium catalyst, successfully undergo high-yielding and highly enantioselective C–H functionalization of hydrocarbons and cyclopropanation of styrene. These products can be used to create not only molecular glue degrader-like compounds but also intermediates that can be elaborated into effective bifunctional ligand-directed degraders. Our findings highlight both the effectiveness of dirhodium catalysis in a drug discovery context and a new method for preparing diverse and stereoenriched glutarimide-containing compounds.