Biocatalytic Transamination for the Asymmetric Synthesis of Pyridylalkylamines. Structural and Activity Features in the Reactivity of Transaminases

A set of transaminases has been investigated for the biocatalytic amination of 1-(4-chloropyridin-2-yl)­alkan-1-ones. The influence of the chain length of the n-1-alkanone at the C-2 position of the pyridine has been studied in the reaction with different (R)- and (S)-selective transaminases. Thus, enantiopure amines were isolated with high purity starting from a wide selection of prochiral ketones. On the one hand, excellent yields (from 97 to >99% conversion, up to 93% isolated yield) and stereoselectivity values (>99% ee for both amine enantiomers) were found for n-1-alkanone linear short chain substituents such as ethanone or propanone. On the other hand, more hindered substrates were accepted only when using evolved enzymes such as an evolved variant of (R)-Arthrobacter (ArRmut11-TA). An initial common structural feature was the presence of a chlorine atom on the C-4 position of the pyridine core, which was found to increase the reactivity of the starting ketone, giving extra versatility for the introduction of other chemical functionalities toward more complex and applicable organic molecules. In order to gain a deeper understanding about the substrate specificity of different transaminases, additional structural features were considered by variation of the acetyl group position on the pyridine ring and the use of related acetophenone derivatives.