Stereoconvergent Photo-Biocatalytic Cascade to Optically Enriched Amines from Racemic Carboxylic Acids

Herein, we report a synergistic synthetic strategy to integrate photoredox catalysis and biocatalysis in a one-pot/two-step linear cascade synthesis of enantiomerically pure amines starting from racemic carboxylic acids utilizing visible light and transaminases. This transformation was achieved via quantitative decarboxylative oxidation (>99% conv.) of racemic aryl-alkyl carboxylic acids followed by stereoselective reductive amination of the corresponding dehomologated carbonyl intermediates. The initial photocatalytic step employs blue LED irradiation (427 nm) and molecular oxygen (O₂) as the terminal oxidant in the presence of 2.5 mol % of sodium anthraquinone-2-sulfonate (SAS) as a water-soluble, metal-free photocatalyst, operating in an aqueous medium containing 2% v/v of acetonitrile (MeCN) or dimethyl sulfoxide (DMSO) as the respective cosolvents. The subsequent transaminase-catalyzed reductive amination of the in situ-generated ketones furnished the desired optically active amines in a stereocomplementary manner with enantiomeric excesses ranging from 93% to 99.9% and up to >99% conversions after two steps. Among the tested substrates, three representative nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, flurbiprofen, and naproxen, were successfully transformed into dehomologated NSAID-derived nonracemic amines with 62->99% ee, respectively. Furthermore, upscaling of the photobiocatalytic process employing 2-(naphthalen-1-yl)-propanoic acid (1.0 mmol) as the substrate enabled the synthesis of (R)-1-(naphthalen-1-yl)-ethan-1-amine with 92% product formation and >99% ee. Finally, a one-step transformation of the aforementioned amine using a recently developed betaine-based Mitsunobu reagent furnished the enantiomerically pure calcimimetic drug cinacalcet (>99% ee) in 76% isolated yield, without the need for transition metal catalysts and/or hazardous and flammable hydrogen gas.