Deoxygenative radical cross-coupling of C(sp3)−O/C(sp3)−H bonds promoted by hydrogen-bond interaction

Yue Wang, Suping Zhang, Ke Zeng, Pengli Zhang, Xiaorong Song, Tie-Gen Chen () and Guoqin Xia ()
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Yue Wang: Southern Medical University
Suping Zhang: Chinese Academy of Sciences
Ke Zeng: Chinese Academy of Sciences
Pengli Zhang: Chinese Academy of Sciences
Xiaorong Song: Chinese Academy of Sciences
Tie-Gen Chen: Southern Medical University
Guoqin Xia: Southern Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-8

Abstract: Abstract Building C(sp3)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp3)−H and C(sp3)−O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form C(sp3)−C(sp3) bonds is rarely explored in existing literature. Conventional methods for forming C(sp3)−C(sp3) bonds via radical-radical coupling pathways often suffer from poor selectivity, severely limiting their practicality in synthetic applications. In this study, we present a single electron transfer (SET) strategy that enables the cleavage of amine α-C − H bonds and heterobenzylic C − O bonds to form C(sp3)−C(sp3) bonds. Preliminary mechanistic studies reveal a hydrogen bond interaction between substrates and phosphoric acid facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.

Date: 2024
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DOI: 10.1038/s41467-024-50897-7

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