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

• Published in: ChemCatChem 2019-09, Vol.11 (17), p.4281-4285
• Main Authors: Matzel, Philipp, Wenske, Sebastian, Merdivan, Simon, Günther, Sebastian, Höhne, Matthias
• Format: Article
• Language: English
• Subjects: Aldehydes; Amines; Biocatalysis; Conversion; Dynamic Kinetic Resolution; Enantiomers; Fungicide; Imine Reductase; Ketones; Nitrogen; Optical activity; Reductases; Substrates; Synthesis; β-chiral Amine
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.201900806

Imine reductases (IREDs) allow the one‐step preparation of optically active secondary and tertiary amines by reductive amination of ketones. Until now, mainly α‐chiral amines have been prepared by this route. In this study, we explored the possibility of synthesizing β‐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 α‐chiral amine synthesis. For investigating the proof of concept, we first confirmed that different IREDs are able to convert a variety of α‐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 β‐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 β‐chiral amines, but also the challenge to identify highly selective enzymes for a desired amine product. From aldehydes to amines: Here, the proof of concept for enzymatic β‐chiral secondary amine synthesis via dynamic kinetic resolution (DKR) employing imine reductases is demonstrated.