Stereodivergent Sequential One‐Pot/Two‐Step Photo‐Biocatalytic Cascade for the Synthesis of Enantioenriched 1‐Arylalkan‐1‐ols From α‐Methylstyrenes

Artificial photo‐biocatalytic cascades offer an attractive platform for the sustainable and selective synthesis of high‐value chiral molecules. Here, we report a sequential one‐pot/two‐step cascade that integrates metal‐free photoredox catalysis with alcohol dehydrogenase (ADH)‐mediated bioreduction to synthesize enantioenriched 1‐arylalkan‐1‐ols from α‐methylstyrenes as the ( R )‐ or ( S )‐enantiomer, depending on the enzyme used. The cascade proceeds through metal‐free, fluorenone‐catalyzed oxidative CC bond cleavage under visible light irradiation, generating the corresponding prochiral ketones, which are subsequently converted into enantioenriched alcohols via stereoselective carbonyl reduction catalyzed by stereocomplementary ADHs. Optimization of the reaction conditions enabled the efficient synthesis of a broad range of chiral 1‐aryl‐substituted sec ‐alcohols with excellent stereoselectivity (up to >99% ee) and moderate‐to‐quantitative conversions (36%–>99%). The synthetic utility of the cascade was demonstrated on a preparative scale using 1‐bromo‐4‐(prop‐1‐en‐2‐yl)benzene (1.0 mmol, ca. 63 mM in 16.0 mL) as the model substrate, affording ( S )‐alcohol in 38% isolated yield and >99% ee when ADH‐A was used as a biocatalyst and the mirror‐image ( R )‐alcohol in 33% isolated yield and >99% ee when employing Lk ADH. This study highlights the potential of combining photoredox catalysis and biocatalysis to enable operationally simple photo‐biocatalytic cascade processes for the stereodivergent synthesis of valuable chiral alcohols from readily available alkene feedstocks.