Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril

The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chemical steps lead to the isolation of captopril in only 75 min. In-line quenching and liquid-liquid separation enable breaks in the workflow and other manipulations to be avoided.