C–N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis

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 (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.

DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output

“…Simmons' group recently developed new DNAcompatible conditions for the formation of the C-N bond. 56 The DNA-tagged aryl halogen (i.e., Cl, Br, and I) coupled with anilines and 2 amines under N-heterocyclic carbene-palladium catalyst, which was used to construct the DEL that contained 63 million molecules (Table 4 ] 2 ) catalysis. The yield of monosubstituted products was better than that of multisubstituted products.…”

Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

“…Using a split-and-pool strategy, each individual library of ∼100 million compounds was synthesized with a unique core scaffold. Quality assurance of libraries for selections was ensured through optimization and validation of on-DNA chemistry reactions prior to library synthesis and the precision of our DNA barcode reads using Illumina sequencing after library synthesis ( 13 , 20 – 22 ). These individual DEC-Tec libraries were subsequently pooled and screened as multibillion compound mixtures against His-tagged recombinant bromodomain proteins.…”

Improved Diazo-Transfer Reaction for DNA-Encoded Chemistry and Its Potential Application for Macrocyclic DEL-Libraries

“…The development of DNA-compatible chemical transformations has enabled a larger chemical space to be covered and has been excellently reviewed by Satz et al [ 8 ]. More recent discoveries show that radical chemistry [ 9 ], photochemistry [ 10 , 11 , 12 ], palladium and copper cross coupling reaction [ 13 , 14 , 15 , 16 , 17 ], and reactions carried out in non-aqueous conditions using a solid phase approach are possible [ 18 , 19 ]. Despite these new excellent methods, there is still plenty of need for more methods to further increase the chemical space for DEL.…”