Enantioconvergent Synthesis of Diarylmethane Drugs via Privileged Benzhydrol Intermediates

The benzhydryl motif is a privileged pharmacophore in antihistaminic and neuroactive drugs. We present a broadly applicable, enantioconvergent synthesis of benzhydrols via asymmetric migratory Tsuji-Wacker oxidation of stilbenes. This constitutionally stereodivergent protocol operates without preactivated or sterically biased substrates, affording chiral α,α-diaryl ketones in up to 91% <i>ee</i>, which convert to benzhydrols without erosion of stereochemistry. The method enables concise syntheses of (<i>S</i>)-cloperastine and isotopically labeled (<i>S</i>)-diphenhydramine-<i>d</i>₅, establishing chiral benzhydrols as versatile intermediates for redox- and step-economic drug assembly.