Stereoselective Bio-Organocatalytic Cascade to Chiral Amides as Active Pharmaceutical Ingredient Intermediates Using...

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.