DNA-encoded library (DEL) technology features a time- and cost-effective interrogation format for the discovery of therapeutic candidates in the pharmaceutical industry. To develop DEL platforms, the implementation of water-compatible transformations that facilitate the incorporation of multifunctional building blocks (BBs) with high C(sp3) carbon counts is integral for success. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated trifluoromethyl-substituted alkenes enabled by single-electron transfer (SET) and subsequent hydrogen atom termination through electron donor–acceptor (EDA) complex activation is detailed. In a further photoredox-catalyzed hydroarylation protocol, the coupling of functionalized, electronically unbiased olefins is achieved under air and within minutes of blue light irradiation through the intermediacy of reactive (hetero)aryl radical species with full retention of the DNA tag integrity. Notably, these processes operate under mild reaction conditions, furnishing complex structural scaffolds with a high density of pendant functional groups.

/pdf/photoredox-mediated-hydroalkylation-and-hydroarylation-of-5ads854sby.pdf

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis.

Recently, DNA-encoded library (DEL) technology has emerged as an innovative screening modality for the rapid discovery of therapeutic candidates in pharmaceutical settings. This platform enables a cost-effective, time-efficient, and large-scale assembly and interrogation of billions of small organic ligands against a biological target in a single experiment. An outstanding challenge in DEL synthesis is the necessity for water-compatible transformations under ambient conditions. To access uncharted chemical space, the adoption of photoredox catalysis in DELs, including Ni-catalyzed manifolds and radical/polar crossover reactions, has enabled the construction of novel structural scaffolds through regulated odd-electron intermediates. Herein, a critical discussion of the validation of photoredox-mediated alkylation in DEL environments is presented. Current synthetic gaps are highlighted and opportunities for further development are speculated upon.

Developments in Photoredox-Mediated Alkylation for DNA-Encoded Libraries.

Synthetic Studies toward DNA-Encoded Heterocycles Based on the On-DNA Formation of α,β-Unsaturated Ketones.

Functionalization of DNA-Tagged Alkenes Enabled by Visible-Light-Induced C–H Activation of N-Aryl Tertiary Amines

Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.

A DNA-encoded chemical library (DECL) is built with combinatorial chemistry, which works by bringing chemical fragments together to generate diverse structures. However, chemical diversity of DNA-encoded chemical libraries is often limited by DNA compatible synthetic reactions. This report shows a conceptual strategy to expand chemical space of DNA-encoded chemical libraries by incorporation of diversity-oriented synthesis in DECL synthesis. We developed Aldol reactions on DNA in a combinatorial way. After obtaining DNA-tagged α , β -unsaturated ketones which represent important chemical intermediates, many distinct structures with skeletal diversities are achieved by diversity-oriented synthesis.

Exploring Aldol Reactions on DNA and Applications to Produce Diverse Structures: An Example of Expanding Chemical Space of DNA‐Encoded Compounds by Diversity‐Oriented Synthesis

Rongfeng Wu

Papers

Functionalization of DNA-Tagged Alkenes Enabled by Visible-Light-Induced C–H Activation of N-Aryl Tertiary Amines

Exploring Aldol Reactions on DNA and Applications to Produce Diverse Structures: An Example of Expanding Chemical Space of DNA‐Encoded Compounds by Diversity‐Oriented Synthesis