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

Jie Wang, Helena Lundberg, Shota Asai, Pedro Martín-Acosta, Jason S. Chen, Stephen Brown, William Farrell, Russell G. Dushin, Christopher J. O’Donnell, Anokha S. Ratnayake, Paul Richardson, Zhiqing Liu, Tian Qin, Donna G. Blackmond, Phil S. Baran

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

DNA-encoded libraries (DEL)-based discovery platforms have re cently been widely adopted in the pharmaceutical industry, mainl due to their powerful diversity and incredible number of mole cules. In the two decades since their disclosure, great strides hav been made to expand the toolbox of reaction modes that are com patible with the idiosyncratic aqueous, dilute, and DNA-sensitiv parameters of this system. However, construction of highly impor tant C(sp3)−C(sp3) linkages on DNA through cross-coupling remain unexplored. In this article, we describe a systematic approach t translating standard organic reactions to a DEL setting throug the tactical combination of kinetic analysis and empirical screenin with information captured from data mining. To exemplify thi model, implementation of the Giese addition to forge high valu C–C bonds on DNA was studied, which represents a radical-base synthesis in DEL.

Original languageEnglish (US)
Pages (from-to)E6404-E6410
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number28
DOIs
StatePublished - Jul 10 2018
Externally publishedYes

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Keywords

  • Combinatorial chemistr
  • DNA-encoded libraries
  • Kinetic analysis
  • Organic synthesis
  • Radical reactions

ASJC Scopus subject areas

  • General

Cite this

Wang, J., Lundberg, H., Asai, S., Martín-Acosta, P., Chen, J. S., Brown, S., Farrell, W., Dushin, R. G., O’Donnell, C. J., Ratnayake, A. S., Richardson, P., Liu, Z., Qin, T., Blackmond, D. G., & Baran, P. S. (2018). Kinetically guided radical-based synthesis of C(sp3)−C(sp3) linkages on DNA. Proceedings of the National Academy of Sciences of the United States of America, 115(28), E6404-E6410. https://doi.org/10.1073/pnas.1806900115