DNA-encoded library (DEL) technology has emerged as a powerful screening modality for the rapid identification of therapeutic candidates in the pharmaceutical industry. DELs are composed of small organic ligands covalently conjugated with a DNA tag that functions as a molecular identifier or barcode for each embedded subunit. Featuring a time-saving and cost-effective interrogation format of billions of drug-like compounds, extremely large combinatorial libraries can be assembled through split-and-pool synthetic routines and subsequently screened against a biological target in a single experiment. An outstanding challenge in DEL synthesis is the necessity for water- and air-compatible reactions under ambient conditions. To increase the chemical diversity of DEL platforms and their C(sp3)-carbon counts, recent research efforts have enabled the implementation of photoredox catalysis, including Ni-catalyzed cross-couplings and radical/polar crossover manifolds, to successfully incorporate diverse alkyl radical precursors in DEL synthesis. First, the use of structurally diverse building blocks, namely organosilanes and aliphatic bromides, in cross-coupling with DNA-conjugated aryl- and heteroaryl bromides is described. In a further protocol, α-silylamines were subjected to radical/polar crossover defluorinative alkylation processes to access <i>gem-</i>difluoroethylene motifs from on-DNA trifluoromethyl-substituted alkenes. In particular, these structural scaffolds have been proposed to function as metabolically stable carbonyl isosteres in medicinal settings. In subsequent studies, the incorporation of carboxylic acid feedstocks to enable the alkylation of on-DNA trifluoromethyl-substituted alkenes to exclusively access benzylic trifluoromethyl groups is achieved through electron donor-acceptor (EDA) photoactivation. Notably, all developed protocols are completed within minutes and do not require an inert atmosphere or any special handling procedure, providing an exceedingly low barrier to practical implementation. The reported studies demonstrate the diverse nature of amenable radical precursors enables the introduction of multifunctional building blocks primed for derivatization in library settings.

Photoredox-mediated alkylation for DNA-encoded libraries

ACS Spring Meeting 2021

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