Yingchu Chen; John Faver; Angela F. Ku; Gabriella Miklossy; Kevin Riehle; Kurt M. Bohren; Melek N. Ucisik; Martin M. Matzuk; Zhifeng Yu; Nicholas Simmons
Bioconjugate Chem., 2020, 31, 3, 770-780
https://doi.org/10.1021/acs.bioconjchem.9b00863

Abstract

DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify chemical starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C–N coupling is a valuable synthetic method for the construction of DECL chemical matter—however currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide and bromide electrophiles. We developed conditions utilizing an N-heterocyclic carbene–palladium catalyst that extends this reaction to the coupling of DNA-conjugated (hetero)aromatic chlorides with (het-ero)aromatic and select aliphatic amine nucleophiles. In addition we evaluated steric and electronic effects within this catalyst series, carried out a large substrate scope study on two representative (hetero)aryl bromides, applied this newly-developed method within the construction of a 63 million-membered DECL and further validated reaction success through the identification of active hits from a screen of this DECL against the target polo-like kinase 1