Biocatalytic Stereodivergent Synthesis of Substituted Tetrahydro‐Benzo‐(Oxa, Thia, and Di)‐Azepines

Benzo-fused seven-membered N,O-, N,S- and N,N-containing heterocyclic moieties are found in several marketed drugs and biologically active molecules. However, the asymmetric synthesis of such heterocycles is limited to the use of transition metal catalysts or chiral phosphoric acids. In the current work, imine reductases (IREDs) are utilized to develop a general biocatalytic method for the stereodivergent synthesis of 5-substituted tetrahydro-1,4-benzoxazepines, 4-substituted tetrahydro-1,5-benzothiazepines, and 2,2,4-trisubstituted tetrahydro-1,5-benzodiazepines in excellent yields (up to 96 %), enantiomeric excess (up to >99 %) and diastereoselectivity (up to >99 %). In addition, imine reductase assisted reductive amination gave facile access to 2,4-disubstituted tetrahydro-1,5-benzodiazepines starting from 1,3-diketone and 1,2-diamino benzene with excellent stereoselectivity and high yields. The absolute configuration of the newly synthesized N-heterocycles was determined using vibrational circular dichroism (VCD). The presented methodology has further broadened the scope of IREDs towards the preparation of chiral seven-membered N-heterocycles containing another heteroatom.