C-N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis.,Bioconjugate Chemistry

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C-N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-02-21 , DOI: 10.1021/acs.bioconjchem.9b00863
Ying-Chu Chen ₁ , John C Faver ₁ , Angela F Ku ₁ , Gabriella Miklossy ₁ , Kevin Riehle ₁ , Kurt M Bohren ₁ , Melek N Ucisik ₁ , Martin M Matzuk ₁ , Zhifeng Yu ₁ , Nicholas Simmons ₁

Affiliation

DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify chemical starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C-N coupling is a valuable synthetic method for the construction of DECL chemical matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide and bromide electrophiles. We developed conditions utilizing an N-heterocyclic carbene-palladium catalyst that extends this reaction to the coupling of DNA-conjugated (hetero)aromatic chlorides with (hetero)aromatic and select aliphatic amine nucleophiles. In addition, we evaluated steric and electronic effects within this catalyst series, carried out a large substrate scope study on two representative (hetero)aryl bromides, and applied this newly developed method within the construction of a 63 million-membered DECL.

中文翻译：

DNA缀合的（杂）芳基溴化物和氯化物的CN偶联，用于DNA编码的化学文库合成。

DNA编码的化学文库（DECL）筛选是一种快速经济的工具，可识别用于药物发现的化学起点。钯催化的CN偶联作为一种强大的药物发现转化方法，是构建DECL化学物质的有价值的合成方法。然而，目前公开的方法仅在附有DNA的（杂）芳族碘化物和溴化物亲电试剂上得到证实。我们开发了利用N-杂环卡宾-钯催化剂的条件，该催化剂将这一反应扩展到DNA共轭（杂）芳族氯化物与（杂）芳族和精选脂肪族胺亲核试剂的偶联。此外，我们评估了该催化剂系列中的空间和电子效应，对两种代表性的（杂）芳基溴化物进行了大范围的底物研究，

更新日期：2020-02-23

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