Dynamic radical recombination enabling stereodivergent construction of spirocycles with nonadjacent stereocenters

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.