Benzazepine motifs are of great pharmaceutical importance due to their presence in many marketed drugs. However, due to a lack of general asymmetric methodology, access to chiral substituted tetrahydro-1-, 2-, and 3-benzazepines remained limited. In the current work, we report the development of a general biocatalytic method using imine reductases (IREDs) for the synthesis of variously substituted chiral tetrahydro benzazepines. The reduction of seven-membered prochiral cyclic imines mainly by imine reductases from Streptomyces sp. GF3587, Kribbella catacumbae and Cystobacter ferrugineus, gave access to preparative scale synthesis of (R)-and/or (S)-specific substituted tetrahydro-1-, 2-, and 3-benzazepines (65 examples) in enantiomeric excess (up to >99%) and isolated yield (up to 96%). In addition, the kinetic parameters and docking studies of the selected imine reductases provided useful insights into the catalytic efficiency and binding of substrates at the active site, respectively. The presented methodology shows the utility of IREDs toward the preparation of chiral benzoannulated seven-membered N-heterocycles, which remain underexplored previously.

Flavoskyrins, (−)-rugulosin B, C and rugulin analogues are synthesized chemoenzymatically from anthraquinones in two, three and four steps, respectively.