Visible light-initiated radical 1,3-difunctionalization of β,γ-unsaturated ketones

• Published in: Science advances Vol. 8; no. 49; p. eabq8596
• Main Authors: Liu, Ruihua, Tian, Yang, Wang, Jie, Wang, Zemin, Li, Xiangqian, Zhao, Chenyang, Yao, Ruoyu, Li, Shuo, Yuan, Leifeng, Yang, Jinbo, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 09.12.2022
• Subjects: Chemistry; Organic Chemistry; Physical and Materials Sciences; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abq8596

Radical-mediated 1,2-difunctionalization of olefins is a well-established synthetic technique widely used in the rapid construction of structurally diverse molecular entities. However, radical-mediated 1,3-difunctionalization reactions are rare, and the substrates are generally limited to strained skeletons. Here, we report a practical approach for 1,3-difunctionalization of available β,γ-unsaturated ketones via a radical cascade process including visible light-irradiated radical addition, thermodynamic stability-driven 1,2-carbonyl migration from unactivated all-carbon quaternary center, and terminal C-radical varied transformations. Various highly functionalized alkyl skeletons with different valuable functional groups at positions 1 and 3 and the carbonyl group at position 2 have been synthesized through a radical chain pathway or Cu-catalyzed Ritter-type reaction. Moreover, this protocol provides a real case of diversity-oriented radical rearrangement for drug discovery. We identified a previously unknown chemotype of dual inhibitors for hypoxia-inducible factor (HIF) and WNT signaling pathways from products. These small-molecule inhibitors could suppress HIF and WNT signaling-dependent HCT116 cell growth in 2D and 3D culture systems.