Preparation of optically pure flurbiprofen via an integrated chemo-enzymatic synthesis pathway

Abstract In the synthesis of chiral molecules, the incorporation of enantioselective enzymatic conversions within the synthetic route often presents a useful approach. For the substitution of a chemical step with an enzymatic reaction, however, the complete synthetic route leading to and from this reaction needs to be considered carefully. An integrated approach, taking the possibilities and challenges of both types of conversions into account, can give access to chemo-enzymatic processes with great potential for effective synthesis strategies. We here report on the synthesis of enantiopure flurbiprofen using arylmalonate decarboxylase (AMDase, EC 4.1.1.76) in a chemo-enzymatic approach. Interestingly, practical considerations required shifting the enzymatic step to an earlier position in the synthetic route than previously anticipated. Engineered enzyme variants made it possible to obtain both ( R )- and ( S )-enantiomers of the target compound in excellent optical purity (>99% ee ). The presented results underline that enzymes are most useful when they fit in a synthetic route, and that the optimization of biocatalytic steps and the planning of synthetic routes should be an integrated process.