bc9b00863_si_001.pdf (13.26 MB)
C–N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis
journal contribution
posted on 2020-02-21, 16:49 authored by Ying-Chu Chen, John C. Faver, Angela F. Ku, Gabriella Miklossy, Kevin Riehle, Kurt M. Bohren, Melek N. Ucisik, Martin M. Matzuk, Zhifeng Yu, Nicholas SimmonsDNA-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 (hetero)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, and applied this newly developed method within the construction
of a 63 million-membered DECL.