Carbene-Mediated Kinetic Resolution Reveals (1S,2R,4R)-Cinmethylin as the Herbicidal Eutomer

Global spread of weeds resistant to conventional herbicide modes of action threatens sustainable weed management. Cinmethylin, a decades-old herbicide with a unique molecular basis, has re-emerged for controlling resistant grass weeds, but remains commercialized as an enantiomeric mixture owing to challenges in asymmetric 1,4-cineole construction and unclear stereoselective bioactivity. Here, we report an efficient chiral N-heterocyclic carbene-mediated kinetic resolution of 2-hydroxy-1,4-cineole, a key cinmethylin precursor. X-ray crystallography establishes the absolute configurations of both enantiomers, which are converted into enantiomer-enriched cinmethylin. Herbicidal assays against ten grass weeds, crop safety tests, receptor binding, and multiomics analyses identify (1S,2R,4R)-cinmethylin as the eutomer, with superior pre- and postemergence activity and excellent crop selectivity. It more strongly inhibits and binds fatty acid thioesterase via Arg176, blocking fatty acid release and reprogramming hormone signaling. This work enables optimized cinmethylin use and reduces inactive distomer inputs.