Biocatalytic routes to enantiomerically enriched dibenz[c,e]azepines

DOI: 10.1002/anie.201708453

Authors: Scott P. France (University of Manchester) , Godwin A. Aleku (University of Manchester) , Mahima Sharma (University of York) , Juan Mangas-sanchez (University of Manchester) , Roger M. Howard (Pfizer Worldwide Research and Development) , Jeremy Steflik (Pfizer Worldwide Research and Development) , Rajesh Kumar (Pfizer Worldwide Research and Development) , Ralph W. Adams (University of Manchester) , Iustina Slabu (University of Manchester) , Robert Crook (Pfizer Worldwide Research and Development) , Gideon Grogan (University of York) , Timothy W. Wallace (University of Manchester) , Nicholas J. Turner (University of Manchester)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 56 , PAGES 15589 - 15593

State: Published (Approved)
Published: November 2017

Abstract: Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω‐transaminase (ω‐TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of (R)‐ and (S)‐5‐methyl‐6,7‐dihydro‐5H‐dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω‐TA biocatalysts were also successfully employed for the production of enantiopure 1‐(2‐bromophenyl)ethan‐1‐amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework.

Journal Keywords: biocatalysis; heterocycles; reductases; synthetic methods; transaminases

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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