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Kinetically guided radical-based synthesis of C(sp3)-C(sp3) linkages on DNA.

ABSTRACT: DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.

SUBMITTER: Wang J 

PROVIDER: S-EPMC6048552 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Kinetically guided radical-based synthesis of C(sp<sup>3</sup>)-C(sp<sup>3</sup>) linkages on DNA.

Wang Jie J   Lundberg Helena H   Asai Shota S   Martín-Acosta Pedro P   Chen Jason S JS   Brown Stephen S   Farrell William W   Dushin Russell G RG   O'Donnell Christopher J CJ   Ratnayake Anokha S AS   Richardson Paul P   Liu Zhiqing Z   Qin Tian T   Blackmond Donna G DG   Baran Phil S PS  

Proceedings of the National Academy of Sciences of the United States of America 20180626 28

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp<sup>3</sup>)-C(sp<sup>3</sup>) linkages o  ...[more]

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