Reductive aminations by imine reductases: from milligrams to tons

The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry. Asymmetric reductive amination for the formation of chiral amines, which are required for the synthesis of pharmaceuticals and other bioactive molecules, is often achieved through transition metal catalysis, but biocatalytic methods of chiral amine production have also been a focus of interest owing to their selectivity and sustainability. The discovery of asymmetric reductive amination by imine reductase (IRED) and reductive aminase (RedAm) enzymes has served as the starting point for a new industrial approach to the production of chiral amines, leading from laboratory-scale milligram transformations to ton-scale reactions that are now described in the public domain. In this perspective we trace the development of the IRED-catalyzed reductive amination reaction from its discovery to its industrial application on kg to ton scale. In addition to surveying examples of the synthetic chemistry that has been achieved with the enzymes, the contribution of structure and protein engineering to the understanding of IRED-catalyzed reductive amination is described, and the consequent benefits for activity, selectivity and stability in the design of process suitable catalysts.

Automated summary

The synthesis of chiral amines through the reductive amination reaction is a significant reaction in synthetic chemistry, with applications in pharmaceutical and bioactive molecule synthesis. While transition metal catalysis is commonly used, biocatalytic methods have gained interest due to their selectivity and sustainability. The discovery of imine reductase and reductive aminase enzymes has paved the way for an industrial approach to chiral amine production, enabling scale-up from laboratory to ton-scale reactions.