Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines

Abstract

DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C−N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C−N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

Impact of Cross-Coupling Reactions in Drug Discovery and Development

“…For cross-coupling reactions, the Suzuki-Miyaura C-C coupling has been demonstrated in an example from the GlaxoSmithKline (GSK) group [55] towards hit identification of phosphoinositide 3-kinase α (PI3Kα) ligands, preparing a three-cycle library of over 3.5 million of diverse compounds. More recently, Torrado and colleagues [56] developed a methodology to tackle, for the first time, the C-N cross-coupling on DNA. Through a series of parallel screening conditions, the group identified mild and efficient reaction conditions for the n-arylation of anilines on-DNA aryl bromides.…”

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

“…In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.…”

“…Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis.…”

Screening of Three Transition Metal‐Mediated Reactions Compatible with DNA‐Encoded Chemical Libraries

“…There have been recent investigations on the implementation of these reactions on substrates coupled to double-stranded DNA fragments. [24,[32][33][34][35][36][37][38][39][40] However, it is often convenient to construct libraries using single-stranded DNA fragments, as these molecular assemblies can be expanded using encoding selfassembling chemistry (ESAC) [16 -21] or used for innovative screening techniques (e. g., interaction-dependent PCR [41] or the hybridization with complementary oligonucleotide-photocrosslinker conjugates. [42,43] In principle, the DNA-compatibility of a reaction could be different for single-and double-stranded DNA derivatives, due to the different shielding of the bases.…”