Nitroreductase-triggered indazole formation

TL;DR

This paper introduces a new enzymatic method to create indazoles, important drug scaffolds, using nitroreductases under mild conditions.

Contribution

The paper presents the first enzymatic route to synthesize indazoles via nitroreductase-triggered reactions.

Findings

Two nitroreductases efficiently convert 2-nitrobenzylamine derivatives to indazoles with >99% conversion.

The method allows for the synthesis of both 1H- and 2H-indazoles depending on the substrate.

A sequential cascade with imine reductase enables the production of 2H-indazoles from inexpensive starting materials.

Abstract

Biocatalysis contributes significantly to the development of more sustainable synthetic pathways by using mild reaction conditions and water as a solvent. However, many relevant classes of compounds, including privileged groups in drug design, are not yet accessible via enzymatic pathways. In this context, the development of an enzymatic route to indazoles remains an unmet challenge. Here, we present a nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles. Two nitroreductases accept a series of 2-nitrobenzylamine derivatives with excellent conversions (up to >99 %). In the case of N-substituted nitrosobenzylamines, 2H-indazoles are formed, whereas other derivatives led to 1H-indazoles. The synthetic value of the nitroreductase-triggered indazole formation is further demonstrated by successful coupling with an imine reductase in a sequential cascade reaction on a 50 mg scale. With this cascade, 2H-indazoles are accessible from cheap 2-nitrobenzaldehyde and primary amines, resulting in up to 85 % conversion and 68 % isolated yield.

An enzymatic route to indazoles, scaffolds present in many drugs, has not been developed yet. Here, the authors report nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles.

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