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

被引：48

作者：

Chen, Ying-Chu ^{[1
]}

Faver, John C. ^{[1
]}

Ku, Angela F. ^{[1
]}

Miklossy, Gabriella ^{[1
]}

Riehle, Kevin ^{[1
]}

Bohren, Kurt M. ^{[1
]}

Ucisik, Melek N. ^{[1
]}

Matzuk, Martin M. ^{[1
]}

Yu, Zhifeng ^{[1
]}

Simmons, Nicholas ^{[1
]}

机构：

[1] Baylor Coll Med, Ctr Drug Discovery, Dept Pathol & Immunol, Houston, TX 77030 USA

来源：

BIOCONJUGATE CHEMISTRY | 2020年 / 31卷 / 03期

基金：

美国国家卫生研究院;

关键词：

CATALYZED AMINATION; BOND FORMATION; PALLADIUM; PD; SELECTION; DESIGN; DISCOVERY; LIGANDS; WATER;

D O I：

10.1021/acs.bioconjchem.9b00863

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：770 / 780

页数：11

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