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.