Work

An Engineered Biocatalyst for Enantioselective Hydrazone Reduction

Year: 2025

Type: article

Abstract: Enantioselective reduction of hydrazones provides a convergent and versatile route to synthesize hydrazine-containing motifs that are commonly found in pharmaceuticals and agrochemicals. However current methods require the use of precious metals, costly chiral ligands and/or forcing reaction conditions. Here, we report the development of a biocatalytic approach for enantioselective hydrazone reduction using engineered imine reductases. Following evaluation of an in-house panel of >400 IRED sequences, we identified a single IR361 I127F L179V variant that promotes reduction of Cbz-protected hydrazones. Introduction of an additional two mutations via directed evolution afforded HRED1.1 that is 20-fold more active than the parent template and promotes reduction of a variety of protected hydrazones in high yields and selectivities (>99% e.e.), including in preparative scale biotransformations. Structural analysis of HRED1.1 provides insights into the origins of its unique hydrazone reductase activity. This study offers a powerful biocatalytic route to synthesize valuable chiral hydrazine products and further expands the impressive range of transformations accessible with engineered imine reductases.

Source: White Rose Research Online (University of Leeds, The University of Sheffield, University of York)