Reductive aminations by imine reductases: from milligrams to tons

• Published in: Chemical science (Cambridge) Vol. 13; no. 17; pp. 4697 - 4713
• Main Authors: Gilio, Amelia K, Thorpe, Thomas W, Turner, Nicholas, Grogan, Gideon
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 04.05.2022; The Royal Society of Chemistry
• Subjects: Amines; Asymmetry; Carbonyl compounds; Carbonyls; Catalysis; Chemical synthesis; Chemistry; Enzymes; Industrial applications; Production methods; Public domain; Reductases; Selectivity; Transition metals
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc00124a

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. IRED-catalyzed reductive aminations have progressed from mg to ton scale, through advances in enzyme discovery, protein engineering and process biocatalysis.