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submitted on 05.01.2020 and posted on 08.01.2020by Zhoulong Fan, Shuai Zhao, Tao Liu, Peng-Xiang Shen, Zi-Ning Cui, Zhe Zhuang, Qian Shao, Jason Chen, Anokha S. Ratnayake, Mark E. Flanagan, Dominik K. Kölmel, David W. Piotrowski, Paul Richardson, jin-quan yu
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 single experiment. To expand the molecular diversity of DEL,
it is critical to develop different types of DNA-encoded transformations that produces
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
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 bifunctional building
blocks, and facilitates access to certain setups for DELs. Furthermore, sequential
C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse
scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane,
cyclobutane, and heterocycles.