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

Abstract

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.

A Regio‐ and Stereoselective ω‐Transaminase/Monoamine Oxidase Cascade for the Synthesis of Chiral 2,5‐Disubstituted Pyrrolidines

“…TAs are capable of mediating the selective reductive amination of prochiral ketones, thereby providing the corresponding chiral amines 3a–e. MAO-N catalyzes the oxygen-dependent conversion of amines into imines and is typically selective for the ( S )-enantiomer 3f–l. Variants of MAO-N have been exploited for the deracemization of primary, secondary, and tertiary amines with diverse structural motifs 3a,f–j.…”

One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

“…Accordingly, a one-pot/two-step methodology allowed the direct conversion of diallyl malonates into cyclic monoacid esters in aqueous media (Scheme 13C). Recently, and following this idea (Ru-catalyzed RCM + enzymatic organic transformations), Turner, Castagnolo and co-workers have reported the combination of the Ru-catalyzed ring-closing metathesis of diallyl anilines (to produce the corresponding 3-pyrrolines) and the subsequent biocatalytic aromatization of the resulting heterocycles (mediated by whole cells containing monoamine oxidases MAO-N variants D5, D9 and D11 [82][83][84] or the nicotine oxidase biocatalyst 6-HDNO (HDNO = 6-hydroxy-D-nicotine oxidase) [85]) for the synthesis of pyrroles in aqueous media (Scheme 14) [77]. In this case, and in contrast to the aforementioned results reported by Gröger, the authors firstly parametrized the biocatalytic transformation, thus studying the aromatization of different 3-pyrrolines promoted by monoamine oxidases MAO-N or 6-HDNO (Scheme 14A).…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…Also, the deracemization of several β-carbolines was achieved with MAO-N-D10 or MAO-N-D11, observing a strong influence on the enzyme stereoselectivity depending on the substitution pattern at position 1 (Scheme 18b). [115] Scheme 18. a) Deracemization of a Levocitirizine motif using a MAO variant and the ammonia-borane complex. [114] b) Deracemization of β-carbolines using MAO-N-D10 and MAO-N-D11.…”