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An amphiphilic polymer-supported strategy enables chemical transformations under anhydrous conditions for DNA-encoded library synthesis.

Ruff, Yves and Martinez, Roberto and Pelle, Xavier and Nimsgern, Pierre and Berst, Frederic and Ratnikov, Max (2020) An amphiphilic polymer-supported strategy enables chemical transformations under anhydrous conditions for DNA-encoded library synthesis. ACS Combinatorial Science, 22 (3). pp. 120-128. ISSN 2156-89522156-8944

Abstract

DNA-encoded libraries have emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection screening methods, the methodology makes it possible to interrogate vast chemical spaces against biological targets of pharmaceutical relevance. Thus, the organic chemistry transformations that can be deployed to the synthesis of encoded libraries play a crucial role in the identification of attractive medicinal chemistry starting points. Unfortunately, these transformations are mostly limited to water-compatible reactions so that the growing oligonucleotide tag can be accommodated. Herein, we describe the development of a catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations in the presence of DNA under anhydrous conditions. We demonstrate the usefulness of this approach by performing several challenging transformations on DNA-small molecule conjugates in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane and the photoreductive Iridium−Nickel dual-catalyzed decarboxylative cross coupling of carboxylic acids to DNA-conjugates aryl halides in multititer-plate format.

Item Type: Article
Keywords: DNA-encoded libraries, SNAP protocol, photodecarboxylative cross coupling, DNA-conjugates
Date Deposited: 17 Nov 2020 00:45
Last Modified: 17 Nov 2020 00:45
URI: https://oak.novartis.com/id/eprint/41934

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