Late-stage functionalization of pharmaceuticals by C–C cross-coupling enabled by wingtip-flexible N-heterocyclic carbenes

IF 11.5 Q1 CHEMISTRY, PHYSICAL
Shiyi Yang, Tongliang Zhou, Xiang Yu, Albert Poater, Josep Duran, Maciej Spiegel, Luigi Cavallo, Steven P. Nolan, Michal Szostak
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引用次数: 0

Abstract

The synthesis of complex molecules by palladium-catalyzed cross-coupling has been pivotal in all stages of drug discovery research. However, this approach has been generally restricted to classical aryl halide electrophiles, requiring the use of a limited pool of precursors. Herein, we report the first highly chemoselective approach to the cross-coupling of bench-stable C–O electrophiles in which abundant phenols can be systematically used as electrophilic cross-coupling partners. Using this approach, we have achieved late-stage functionalization of >20 pharmaceuticals covering various architectures and drug targets. Wingtip-flexible N-heterocyclic carbenes as ancillary ligands enable us to address the major challenges to this mode of catalysis, such as fast oxidative addition to prevent the hydrolysis of C–O electrophiles and facile reductive elimination to establish C–C bond formation in complex settings. The design of wingtip-flexible N-heterocyclic carbene ligands will enable the cross-coupling of a broad range of electrophiles for the development of important medicines.

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来源期刊
CiteScore
10.50
自引率
6.40%
发文量
0
期刊介绍: Chem Catalysis is a monthly journal that publishes innovative research on fundamental and applied catalysis, providing a platform for researchers across chemistry, chemical engineering, and related fields. It serves as a premier resource for scientists and engineers in academia and industry, covering heterogeneous, homogeneous, and biocatalysis. Emphasizing transformative methods and technologies, the journal aims to advance understanding, introduce novel catalysts, and connect fundamental insights to real-world applications for societal benefit.
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