Biocatalytic Access to Chiral Benzazepines Using Imine Reductases

Abstract

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.

Enantioselective Synthesis of Secondary Amines by Combining Oxidative Rearrangement and Biocatalysis in a One-Pot Process

“…Recently, Husain et al also published the enantioselective IRED-catalyzed reduction of 2b and various other benzazepines. However, while they found an efficient IRED producing the ( R )-enantiomer with an excellent ee , in contrast to our work, the highest ee they found for an IRED producing the ( S )-enantiomer was 87% ee …”

“… a Conversion was determined via 1 H NMR spectroscopy. b Enantiomeric excess ( ee ) and absolute configuration were determined via HPLC analysis using a chiral stationary phase. , …”

“…This chemoenzymatic one-pot process running in a sequential mode in aqueous medium opens a new perspective to highly enantiomerically enriched secondary heterocyclic amines. Current efforts address the extension of this approach toward an analogous preparation of a range of 2-aryl-substituted pyrrolidines or tetrahydro-benzazepines that serve as important building blocks or structural motifs in pharmaceuticals. , Furthermore, since the oxidative rearrangement based on the use of secondary amines as starting materials and either hypervalent iodine or NCS-based methods yield iminium ion intermediates, a further current and future work also addresses the combination of such rearrangement reactions with IRED catalysis. The biocatalytic reduction of iminium ions in isolated form has been previously reported in the literature, thus providing a promising starting point to establish such a one-pot route to the corresponding optically pure tertiary amine compounds .…”

“…As for the first task of an asymmetric reduction of imines, imine reductases turned out to represent an excellent type of catalyst for this purpose, providing a sustainable and eco-friendly substitute for conventional chemocatalysts. , In this research field, in 2022 we already reported the enantioselective IRED-catalyzed reduction of 2-aryl-substituted pyrrolines, which are structurally related to those being accessible via oxidative rearrangement ( 2a ). , This now led to the concept of merging the enantioselective, biocatalytic reduction step with oxidative rearrangement as access to these pyrrolines . We selected imine 2b as our second model substrate due to its easy accessibility through oxidative rearrangement and its molecular structure similarity with the imines known to be excellent substrates for IRED-catalyzed reductions, such as dihydroisoquinolines. , Very recently, Husain et al found IREDs converting the chosen imine 2b with high conversion and good to excellent enantiomeric excesses …”

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“…Screening of a range of imine reductases has identified various biocatalysts that can perform the asymmetric reduction of seven-membered cyclic imines for the synthesis of either enantiomer of tetrahydro-1-, 2- and 3-benzazepines. 26 For example, IR-3 from Cystobacter ferrugineus was highly effective for the preparation of chiral tetrahydro-1-benzazepines in excellent yields and enantioselectivities (Scheme 1). Site-directed mutagenesis of an imine reductase has produced an optimal catalyst for reductive amination of a Boc-protected 4-oxoazepine with various amines (Scheme 2).…”