Photo‐Biocatalytic One‐Pot Conversion of 1,1‐Disubstituted Alkenes into Optically Enriched Primary Amines

Merging photocatalysis with biocatalysis has recently emerged as a powerful strategy in chemical synthesis. Whereas photocatalysis enables the generation of reactive intermediates under mild conditions, biocatalysis provides exceptional selectivity with minimal byproducts. Herein, we report a one‐pot/two‐step photo‐biocatalytic oxidation–reductive amination cascade that transforms α ‐methyl terminal alkenes into enantiomerically pure amines. In the initial step, 1,1‐disubstituted (hetero)aryl alkyl olefins underwent oxidative cleavage to prochiral ketones using molecular oxygen under blue‐light irradiation (427 nm) with 9‐fluorenone as a transition‐metal‐free photocatalyst in dimethyl sulfoxide (DMSO), which simultaneously serves as solvent and quencher of in situ generated H 2 O 2 . Subsequent sequential combination with transaminase‐catalyzed reductive amination furnished the targeted nonracemic amines in good‐to‐excellent overall conversions (52%–95%) and high‐to‐excellent enantiomeric excesses (90%–99.9%) in a stereocomplementary manner. The photo‐biocatalytic cascade was successfully scaled up with α ‐methylstyrene (1.0 mmol), enabling the synthesis of the pharmaceutically relevant chiral precursor ( R )‐(+)‐1‐phenylethylamine in 93% conversion, 61% isolated yield, and >99% ee. Further derivatization of this key intermediate delivered the L‐type calcium channel blocker fendiline in 77% isolated yield and 99% ee, without the need for costly transition metal catalysts, hazardous hydrogen gas, and high pressure.