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

• Published in: Nature communications Vol. 15; no. 1; pp. 6745 - 8
• Main Authors: Wang, Yue, Zhang, Suping, Zeng, Ke, Zhang, Pengli, Song, Xiaorong, Chen, Tie-Gen, Xia, Guoqin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/549/933; 639/638/77/890; Amino acids; Bioactive compounds; Biological activity; Chemical bonds; Cleavage; Constraining; Coupling (molecular); Cross coupling; Deoxygenation; Electron transfer; Electrons; Humanities and Social Sciences; Hydrogen bonds; multidisciplinary; Phosphoric acid; Science; Science (multidisciplinary); Single electrons; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50897-7

Building C(sp 3 )-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp 3 )−H and C(sp 3 )−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(sp 3 )−C(sp 3 ) bonds is rarely explored in existing literature. Conventional methods for forming C(sp 3 )−C(sp 3 ) 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(sp 3 )−C(sp 3 ) 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. Conventional methods for forming C(sp3)−C(sp3) bonds via radical-radical coupling pathways often suffer from poor selectivity, limiting their practicality in synthetic applications. Herein, the authors report a single electron transfer strategy that enables the cleavage of amine α-C − H bonds and heterobenzylic C − O bonds to form C(sp3)−C(sp3) bonds.