The structural diversity of DNA Encoded Libraries has been limited since the hydrophilic, anionic, and fuctional group rich nature of the DNA tag severely limits the repertoire of compatible chemical reactions. Rather than pursuing the optimization of individual synthetic organic reactions for water compatibility, we reasoned that a general strategy for transferring DNA-substrates into organic solvents could significantly expand the structural diversity explored by DEL. Reversible absorption of macromolecules to a solid support (RASS) has facilitated peptide and protein modification, enabling the use of anhydrous solvents and multistep synthetic procedures. This RASS strategy was adapted for DEL through a commercially available polystyrene based, quaternary ammonium resin. Adsorption of DNA headpiece substrates to this resin was found to facilitate transfer to organic solvents such as DMA, THF, EtOH, and CH<sub>2</sub>Cl<sub>2</sub>. This RASS approach for DEL has enabled the development of Ni mediated carbon-carbon (C(sp2)-C(sp3)) and carbon-heteroatom (C-N, C-S, C-P) cross couplings with broad substrate scope and DNA compatibility. The immobilization of the DNA has also facilitated the use of diverse reaction manifolds including electrochemical and photochemical transformations. In addition, this approach has been further optimized for use in industrial scale library building. This expanded scope of reaction conditions compatible with DEL library generation has the promise to contribute to the generation of conformationally diverse scaffolds with drug-like properties.

DEL out of water: Expanding DNA compatible chemistry in organic solvents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.