DNA-encoded chemistry translates molecular biology techniques for molecular evolution such as DNA barcoding, selection, DNA amplification, and DNA sequencing to combinatorial small molecule library synthesis and target-based screening. A broad scope of chemical reactions and diverse starting materials is desirable to furnish structurally diverse encoded libraries. Encoded library synthesis in homogeneous systems requires chemical methods that provide DNA-compatibility, water-tolerance and fast kinetics to operate on highly diluted DNA-tagged reactants. Ideally, they are operationally simple and furnish target compounds from diverse starting materials with high yields. Only a very few chemical reactions meet all these demands, access to encoded heterocyclic chemistry is even rare. Micellar catalysis is an attractive principle for encoded compound synthesis due to both reaction acceleration and DNA shielding. Amphiphilic block copolymers formed spherical nanoreactors and immobilized a catalyst in the DNA-inaccessible hydrophobic core. Sulfonic acid-substituted micelles converted DNA-tagged aldehydes by Povarov and Groebke reactions to diverse substituted tetrahydroquinolines and imidazopyridines without noticeable DNA degradation, and facilitated <i>t</i>Boc group removal from amines. Furthermore, a Cu(I)-immobilizing micelle mediated the DNA-compatible oxidation of DNA-tagged alcohols to aldehydes by the Cu(I)/bipyridine/TEMPO system.<br/>Initiating encoded library synthesis with solid phase-coupled barcodes is an alternative to solution-phase encoded chemistry. It benefits from freely selectable organic solvents and nucleobase-protection conferring increased chemical stability to the oligonucleotide tag. A solid phase-initiated barcoding strategy allowed for ready translation of several reactions to encoded library synthesis, among them heterocycle-forming cycloaddition reactions, isocyanide MCR chemistry, and phosphoric acid-mediated reactions.

Reaction development for DNA-encoded library synthesis: Exploring heterogeneous systems

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

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