A Buchwald–Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3‐Ligase PROTACs**
Thomas G. Hayhow, Rachel E. A. Borrows, C. R. Diène, Gary Fairley, Charlene Fallan, Shaun Fillery, James S. Scott, David Watson
Abstract
A palladium-catalysed Buchwald-Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.
Topics & Concepts
CereblonAminationLinkerChemistryBifunctionalCombinatorial chemistryArylAlkylUbiquitin ligaseOrganic chemistryComputer scienceBiochemistryUbiquitinCatalysisProgramming languageGeneProtein Degradation and InhibitorsMultiple Myeloma Research and TreatmentsPeptidase Inhibition and Analysis