Conversion of alcohols to enantiopure amines through dual-enzyme hydrogen-borrowing cascades

Abstract

α-Chiral amines are key intermediates for the synthesis of a plethora of chemical compounds at industrial scale. We present a biocatalytic hydrogen-borrowing amination of primary and secondary alcohols that allows for the efficient and environmentally benign production of enantiopure amines. The method relies on a combination of two enzymes: an alcohol dehydrogenase (from Aromatoleum sp., Lactobacillus sp., or Bacillus sp.) operating in tandem with an amine dehydrogenase (engineered from Bacillus sp.) to aminate a structurally diverse range of aromatic and aliphatic alcohols, yielding up to 96% conversion and 99% enantiomeric excess. Primary alcohols were aminated with high conversion (up to 99%). This redox self-sufficient cascade possesses high atom efficiency, sourcing nitrogen from ammonium and generating water as the sole by-product.

Figure 1

Two-enzyme cascade for the hydrogen-borrowing amination of alcohols. In the first oxidative step, the Prelog AA-ADH and the anti-Prelog LBv-ADH were applied for the oxidation of the (S)- and (R)-configured alcohol substrates, respectively. The AmDHs used in this study afforded the (R)-configured amines in the second reductive step. Alcohol substrates explored in this study are shown below the schematic catalytic cycle.

Fig. 2

Kinetics of asymmetric hydrogen-borrowing biocatalytic amination. The reaction of (S)-1a (20 mM) gives inverted (R)-3a using AA-ADH and Ph-AmDH with catalytic NAD⁺ (1 mM; 5 mol%). Concentrations of the amine product (solid line, black circles), ketone intermediate (dotted line, black squares) and alcohol substrate (dashed line, white circles) were monitored over time. As expected, the concentration of the ketone intermediate 2a remains constant and below the concentration of the nicotinamide coenzyme. For details, see SM paragraph S12.