Monoamine Oxidase (MAO-N) Catalyzed Deracemization of Tetrahydro-β-carbolines: Substrate Dependent Switch in Enantioselectivity

The tetrahydro-β-carboline (THBC) ring system is an important structural motif found in a large number of bioactive alkaloid natural products. Herein we report a broadly applicable method for the synthesis of enantiomerically pure β-carbolines via a deracemization procedure employing the D9 and D11 variants of monoamine oxidase from Aspergillus niger (MAO-N) in combination with a nonselective chemical reducing agent. Biotransformations were performed on a preparative scale, leading to the synthesis of optically enriched products in excellent enantiomeric excess (e.e.; up to 99%) and isolated yield (up to 93%). Interestingly, a switch in enantioselectivity associated with the MAO-N variants is observed as the nature of the C-1 substituent of the THBC is varied. Molecular modeling provided an explanation for this observation and highlighted key active site residues which were modified, resulting in an increase in ( R )-selectivity associated with the enzyme. These results provide insight into the factors which influence the selectivity of the MAO-N variants, and may offer a platform for future directed evolution projects aimed toward the challenge of engineering ( R )-selective amine oxidase biocatalysts.