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Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

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Abstract

DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp3-bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl2-promoted aza-Diels–Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials.

Graphical abstract: Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

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Publication details

The article was received on 18 Sep 2019, accepted on 17 Oct 2019 and first published on 01 Nov 2019


Article type: Edge Article
DOI: 10.1039/C9SC04708E
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

    M. Potowski, F. Losch, E. Wünnemann, J. K. Dahmen, S. Chines and A. Brunschweiger, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC04708E

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