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Merging C(sp3)–H activation with DNA-encoding

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Abstract

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

Graphical abstract: Merging C(sp3)–H activation with DNA-encoding

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Article information


Submitted
18 Jul 2020
Accepted
06 Sep 2020
First published
07 Sep 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Merging C(sp3)–H activation with DNA-encoding

Z. Fan, S. Zhao, T. Liu, P. Shen, Z. Cui, Z. Zhuang, Q. Shao, J. S. Chen, A. S. Ratnayake, M. E. Flanagan, D. K. Kölmel, D. W. Piotrowski, P. Richardson and J. Yu, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC03935G

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