Synthesis of Substituted Acyclic and Cyclic <i>N</i>‐Alkylhydrazines by Enzymatic Reductive Hydrazinations

Imine reductases (IREDs) provide promising opportunities for the synthesis of various chiral amines. Initially, asymmetric imine reduction was reported, followed by reductive aminations of aldehydes and ketones via imines. Herein we present the reductive amination of structurally diverse carbonyls and dicarbonyls with hydrazines (reductive hydrazination), catalyzed by the IRED from Myxococcus stipitatus. In analogy to IRED-catalyzed reductive aminations, various carbonyls and dicarbonyls could react with simple hydrazines to produce substituted acyclic and cyclic N-alkylhydrazines. By incorporating and scaling up a hydrogenase cofactor regeneration system, we demonstrated the scalability and atom-efficiency of an H₂-driven double reductive hydrazination, highlightling the potential of IREDs in biocatalysis.