Dynamic radical recombination enabling stereodivergent construction of spirocycles with nonadjacent stereocenters

Zheng Sun, Jichao Huang, Jiangtao Ren, Kaixin Zhao, Xixiang Chen, Jing Liang, Yifan Li, Fangzhi Peng, Yi Jin (), Yingqing Ou (), Jianrong Xu (), Zhihan Zhang () and Zhihui Shao ()
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Zheng Sun: Yunnan University
Jichao Huang: Central China Normal University
Jiangtao Ren: Yunnan University
Kaixin Zhao: Yunnan University
Xixiang Chen: Shanghai University of Traditional Chinese Medicine
Jing Liang: Yunnan University
Yifan Li: Yunnan University
Fangzhi Peng: Yunnan University
Yi Jin: Yunnan University
Yingqing Ou: National University of Singapore
Jianrong Xu: Shanghai University of Traditional Chinese Medicine
Zhihan Zhang: Central China Normal University
Zhihui Shao: Yunnan University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Chiral spirocyclic scaffolds have garnered significant attention in drug discovery and chiral ligand development due to their rigid structures and potential bioactive properties, yet stereodivergent synthesis of such systems, particularly those bearing non-adjacent stereocenters, remains a formidable challenge. Herein, we report a dynamic radical recombination (DRR) strategy that enables cobalt-hydride-catalyzed ligand-controlled stereodivergent olefin hydroalkylation, delivering a series of spirocyclic compounds bearing 1,3-non-adjacent stereocenters with up to >99:1 er and >20:1 dr. Density functional theory (DFT) calculations reveal that different ligands induce distinct reaction mechanism, resulting in diastereoselectivity reversal through dynamic radical recombination pathway. Biological evaluations demonstrate that selected newly synthesized spirocyclic products markedly suppress lipopolysaccharide (LPS)-induced neuroinflammation in microglial cells, effectively reducing pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) and restoring cells to pre-inflammatory states.

Date: 2025
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DOI: 10.1038/s41467-025-64491-y

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