# Stereoselective Bio‐Organocatalytic Cascade to Chiral Amides as Active Pharmaceutical Ingredient Intermediates Using ω‐Transaminase and Choline Chloride Under Microwave Irradiation

## TL;DR

This paper presents a green and efficient method to create chiral amides, important for pharmaceuticals, using enzymes and microwave conditions.

## Contribution

A solvent-free, microwave-assisted bio-organocatalytic cascade for chiral amide synthesis using ω-transaminases and choline chloride.

## Key findings

- The cascade achieved full conversions and >99% enantiomeric excess for key pharmaceutical intermediates.
- Amidation using choline chloride yielded amides in 60%-86% without traditional activating agents.
- Solvent removal after transamination improved amidation efficiency by eliminating byproducts.

## Abstract

Amide bond formation is a key transformation in organic synthesis, especially for the preparation of active pharmaceutical ingredients (APIs). In this work, we report the development of a bio‐organocatalytic cascade, combining stereoselective transamination catalyzed by ω‐transaminases (ω‐TAs) in neat organic solvent and choline chloride (ChCl)‐mediated direct amidation. This strategy enables the synthesis of chiral amides from prochiral carbonyl compounds and carboxylic acids under solvent‐free microwave conditions. After optimizing the biocatalytic transamination in MTBE, we applied the method to the synthesis of key intermediates of Racecadotril and AVR‐48, achieving full conversions and enantiomeric excess above 99%. The amidation step, promoted by ChCl without traditional activating agents, proved highly efficient for a wide range of aliphatic and aromatic carboxylic acids, affording the target amides in 60%–86% yields. Solvent evaporation after the transamination step was essential to remove interfering byproducts such as acetone, thus improving amidation yields. Overall, this integrated methodology provides a green, efficient, and scalable route to access amide‐based building blocks in high optical purity, opening new avenues for sustainable pharmaceutical manufacturing.

Amide bond formation is central to active pharmaceutical ingredient (API) synthesis. A bio‐organocatalytic cascade is reported, merging stereoselective ω‐transaminase (ω‐TA) transamination in neat organic solvent with choline chloride‐mediated amidation under solvent‐free microwave conditions. The method delivers chiral amides in high yields and >99% ee, enabling efficient, green access to pharmaceutical intermediates such as those of Racecadotril and AVR‐48.© 2026 WILEY‐VCH GmbH