Water-enabled organometallic and enzymatic catalysis: Sustainable technologies supporting API manufacturing

Aqueous chemistry is a key platform for advancing sustainable organometallic and enzymatic catalytic technologies relevant to API manufacturing. Effective implementation requires minimizing Process Mass Intensity, increasing Reaction Mass Efficiency, ensuring final product quality, and managing the impact of water-waste contaminants. Recent advances in palladium cross-coupling show how water or aqueous cosolvents can deliver highly efficient transformations: micellar water/SDS/CPME systems with new monodentate basic phosphines enable 0.125-0.5 mol% Pd and PMIs near 20 on complex architecture, while bidentate nitrogen ligands in HEP/water achieve 0.1-0.005 mol% Pd, TONs up to 17,800, and >90% Pd recovery. Enzymatic innovations, including Merck’s free-enzyme cascade for Islatravir and subtilisin-engineered peptide ligation for Liraglutide, demonstrate how aqueous biocatalysis can provide selective, scalable, and greener API-relevant processes. • Organometallic and enzymatic technologies enable sustainable, cost-competitive processes. • Palladium-catalyzed cross couplings reactions deliver low loading, high TONs, low PMI processes. • The development of new ligands is now targeting efficiency and competitive green metrics. • The integration between enzymatic catalysis in modern organic chemistry is the key for API synthesis.