Enantioconvergent Synthesis of Diarylmethane Drugs via Privileged Benzhydrol Intermediates

TL;DR

A new method for making chiral benzhydrol intermediates is developed, enabling efficient synthesis of diarylmethane drugs.

Contribution

An enantioconvergent synthesis of benzhydrols via asymmetric migratory Tsuji-Wacker oxidation is introduced.

Findings

Chiral α,α-diaryl ketones are obtained with up to 91% ee via asymmetric oxidation.

The method allows for the synthesis of (S)-cloperastine and isotopically labeled (S)-diphenhydramine-d5.

Benzhydrols are established as versatile intermediates for drug assembly.

Abstract

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% ee, which
convert to benzhydrols without erosion of stereochemistry. The method
enables concise syntheses of (S)-cloperastine and
isotopically labeled (S)-diphenhydramine-d
5, establishing chiral benzhydrols as versatile
intermediates for redox- and step-economic drug assembly.

Figures