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

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