Process-intensified enzymatic decarboxylation using immobilized arylmalonate decarboxylase for sustainable asymmetric synthesis of α-arylpropionic acids

Abstract

Enantiopure α-arylpropionic acids are essential pharmaceuticals, yet their biocatalytic synthesis via arylmalonate decarboxylases (AMDases) is hindered by the instability of malonic acid intermediates. Standard saponification requires an acidic workup that triggers spontaneous, non-selective malonate decarboxylation, while alternative hydrogenolysis reactions rely on potentially pyrophoric palladium catalysts. This study presents an integrated, intensified process combining alkaline hydrolysis of dimethyl malonates with enzymatic decarboxylation using an immobilized AMDase. To suppress racemic side-product formation, a reaction setup using a rotating bed reactor with in situ pH-stat control was established, ensuring substrate stability via anionic stabilization. For enzyme immobilization, C2-amino polyacrylate carriers resulted in superior stability, enabling efficient preparative-scale biotransformations. Naproxen and flurbiprofen were obtained with isolated yields up to 96% and high enantiopurity (ee > 99%), leading to a Process Mass Intensity (PMI) of, e.g., 158 kg kg naproxen⁻¹, representing a significant improvement over the current benchmark. Likewise, CO₂ production, as a Global Warming Potential (GWP) indicator, was assessed considering the three main contributors, the energy of the reaction, the decarboxylation process, and the wastewater treatment, with an impact in the range of 32 kg CO₂ kg naproxen⁻¹. Overall, integrating a safe saponification with automated process control and decarboxylases provides a scalable, green(er) framework for producing enantiopure carboxylic acids.