April 2020-1: Accessing pharmaceutically relevant (S)-configured α-chiral amines via kinetic resolution with an amine dehydrogenase

In our previous work (see news of August 2019), we have created new amine dehydrogenase enzymes (AmDHs) by exploiting the protein scaffold of the (ε-deaminating) L-lysine dehydrogenase enzyme (LysEDH) from Gebacillus stearothermophillus. In this new work, one of these engineered NADH‐dependent amine dehydrogenases (LE‐AmDH‐v1) was applied together with a NADH‐oxidase from Streptococcus mutans (NOx) for the kinetic resolution of pharmaceutically relevant racemic α‐chiral primary amines. The reaction conditions (e. g., pH, temperature, type of buffer) were optimised to yield (S)‐configured amines with up to >99 % ee. The oxidative kinetic resolution proceeded efficiently at the optimum pH of 7.4 in 50 mM Tris‐HCl or 100 mM KPi. At 30 °C, the KR reached completion after 16 h and increasing the reaction temperature from 30 °C to 50 °C resulted in the resolution of α‐methylbenzylamine within 8 h. Using these optimal conditions, the kinetic resolution of a number of substituted α‐methylbenzylamines, 1‐aminotetralin, 1‐aminoindane, and 4‐aminochromane was complete in all cases, with the exception of meta-fluoro-α‐methylbenzylamines, which reached 95% enantiomeric excess after 48 h. This work highlights the potential of AmDHs for the highly selective manufacture of API intermediates and the need to discover and engineer new AmDH variants in order to extend substrate scope and synthetic applicability.

Link to Full article (Open Access) can be found here