Biocatalytic Reduction of Heterocyclic Imines in Continuous Flow with Immobilized Enzymes

Heterocyclic amines are regarded as key structural motifs for the synthesis of pharmaceuticals (e.g., antibiotics), as well as pesticides and flavors. In this context, imine reductases (IREDs) have recently been recognized as highly selective and sustainable alternatives for asymmetric reductive amination reactions. In this study, six IREDs, including two newly identified ones, were applied in the reduction of heterocyclic imines bearing N, S, or O substitutions at the C-4 position. As IREDs are NADPH-dependent enzymes, a commercially available, supported glucose dehydrogenase was employed as a cofactor-regenerating system. To further improve the efficiency and sustainability of the system, the IREDs were immobilized on porous microparticles. Through a strategic combination of bioinformatic analysis and immobilization screening, immobilized biocatalysts with 95% retained activity were obtained. This enabled the integration of the bienzymatic system into a continuous-flow reactor, in which >90% conversion of 50 mM of the S-heterocyclic amine, 5-methyl-3,6-dihydro-2H-1,4-thiazine, was achieved with a residence time of 30 minutes, and space-time yields of up to 14.3 g L⁻¹ h⁻¹ were reached. Additionally, (S)- or (R)-stereoselectivity in the biocatalytic reduction of 1,4-disubstituted heterocyclic imines was obtained by employing the newly identified IREDs from Goodfellowiella coeruleoviolacea and Labilithrix luteola, respectively.

• Benitez-Mateos, AI
• Lim, D

• Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern 3012, Switzerland

• Request a Brochure
• Request more Info
• Request a Quote