A Buchwald–Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3‐Ligase PROTACs. Issue 70 (3rd November 2020)

• Record Type: Journal Article
• Authors: Hayhow, Thomas G.; Borrows, Rachel E. A.; Diène, Coura R.; Fairley, Gary; Fallan, Charlene; Fillery, Shaun M.; Scott, James S.; Watson, David W.
• Is Part Of: Chemistry. Volume 26:Issue 70(2020)
• Page Start: 16818
• Page End: 16823
• Publication Date: 2020-11-03
• Subjects: amination -- cereblon -- drug discovery -- PEPPSI -- PROTAC; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202003137
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : PROTAC assembly : A method to introduce diverse amines to lenalidomide‐like scaffolds is described. The products from the Buchwald–Hartwig cross couplings could be used to access a range of PROTACs in a short number of subsequent steps. The coupling is effective from milligram to multigram scale.