One‐Pot Synthesis of Chiral Succinate Dehydrogenase Inhibitors and Antifungal Activity Studies

Abstract In this work, a series of novel chiral succinate dehydrogenase inhibitors (SDHIs) are synthesized through a one‐pot Rh‐catalyzed asymmetric hydrogenation‐condensation strategy. This method exhibits high efficiency (up to 1000 Ton, 94% yield over two steps), high stereoselectivity (up to 99% ee), and broad substrate scope (68 examples in total), providing a superior pathway for the synthesis of such chiral fungicides. Mechanistic studies indicate that the amino group at the 2‐position of the phenyl ring acts as an activating group, enhancing the reactivity and stereoselectivity control of the reaction. Furthermore, these molecules exhibit broad‐spectrum and highly effective antifungal biological activity. Notably, enantiomers show significant differences in both in vitro and in vivo fungi‐inhibiting experiments. Especially, ( S )‐ 5f showcases an antifungal activity against Botrytis cinerea (EC 50 = 0.48 µ m ) that is much higher than that of its R enantiomer (EC 50 = 36.7 µ m ). Molecular docking calculations, molecular dynamic simulation, enzyme activity assays, and ligand‐target interaction experiments demonstrate that ( S )‐ 5f (ΔG MM‐PBSA = −18.86 kcal mol −1 , K D = 6.04 µ m ) inhibits succinate dehydrogenase more effectively than its R enantiomer (ΔG MM‐PBSA = −13.01 kcal mol −1 , K D = 8.5 µ m ). Moreover, the two enantiomers have significantly different effects on spore germination and the destruction of fungal phenotype.