Chiral amines are useful intermediates in organic synthesis, e.g., for the preparation of pharmaceutically active compounds. Biocatalysis is a promising approach to creating such amines under mild conditions and without hazardous reagents. Imine reductases (IREDs), for example, are enzymes that can catalyze the reduction of prochiral imines to chiral amines. Reductive aminases, a subtype of IREDs, can promote reductive aminations of carbonyl compounds in water in the presence of amine donors. However, these enzymes so far provide poor conversions when ammonia is used as the amine source.
Gideon Grogan, University of York, UK, Nicholas J. Turner, University of Manchester, UK, and colleagues have found two reductive aminases that can use ammonia as the amine partner and efficiently catalyze the formation of chiral primary amines (pictured). The reductive aminases, NfRedAm and NfisRedAm, were first isolated from the fungi Neosartorya fumigata and Neosartorya fischeri, respectively. The team first explored the substrate scope of the enzymes using carbonyl compounds such as ketoesters, cyclic ketones, or aliphatic ketones and reacting them with short-chain amines, e.g., propargylamine or allylamine. They found that both enzymes allow the synthesis of chiral secondary amines or lactams from these substrates. The two enzymes achieve similar conversions in this type of reaction.
The team then investigated whether ammonia can be used as the amine source to make primary amines. They found that both NfRedAm and NfisRedAm achieve higher conversions in this reaction than previously used reductive aminases. The enzymes also have a higher thermostability than other enzymes within the same family. According to the researchers, these biocatalysts could have potential for large-scale, industrial applications.
- Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases,
Juan Mangas-Sanchez, Mahima Sharma, Sebastian C. Cosgrove, Jeremy I. Ramsden, James R. Marshall, Thomas W. Thorpe, Ryan B. Palmer, Gideon Grogan, Nicholas J. Turner,
Chem. Sci. 2020.