Synthesis of β-Chiral Amines by Dynamic Kinetic Resolution of α-Branched Aldehydes Applying Imine Reductases

Imine reductases (IREDs) allow the one-step preparation of optically active secondary and tertiary amines by reductive amination of ketones. Until now, mainly alpha-chiral amines have been prepared by this route. In this study, we explored the possibility of synthesizing beta-chiral amines, a class of compounds which is also frequently found as structural motif in pharmaceuticals but much more challenging to prepare due to the following reasons: (i) The aldehyde substrate already contains the chiral center and needs to be racemized to enable full conversion. (ii) Because the intermediate imine bears the stereo center two carbon atoms remote to the imine nitrogen, it is more challenging to achieve high enantioselectivity compared to alpha-chiral amine synthesis. For investigating the proof of concept, we first confirmed that different IREDs are able to convert a variety of alpha-branched aldehydes when combined with five different amine substrates. The IRED from Streptomyces ipomoeae was a suitable enzyme facilitating the dynamic kinetic resolution of 2-phenylpropanal and a substituted 2-methyl-3-phenylpropanal: the corresponding N-methylated beta-chiral amines were obtained with >95 % conversion and 78 and 95 %ee. Other amines were formed with low to moderate enantiomeric excess. This exemplifies the potential of IREDs for the one-step synthesis of secondary beta-chiral amines, but also the challenge to identify highly selective enzymes for a desired amine product.