The combination of metal- and biocatalysis is a challenging but forward-looking topic in synthetic chemistry. The unique selectivity of enzymes paired with the broad range of applications of chemical catalysts enables an undreamed-of number of novel processes. Herein, we describe the application of immobilized phenolic acid decarboxylase (PAD) for the decarboxylation of para-coumaric acid and subsequent Pd-catalyzed Heck cross-coupling with an aryl halide in a fully integrated two-step continuous flow process to synthesize (E)-4-hydroxy-stilbene. The application of a choline chloride-based deep eutectic solvent (DES) proved to be crucial to overcome the problem of solvent compatibility and enabled an increase in substrate concentration (from 5 mM in buffer to 20 mM in DES) as well as a process with a homogeneous starting solution. The two-step process was successfully operated for more than 16 h in continuous flow and full conversion was achieved. The results underline the usefulness of DES to overcome compatibility problems in tandem-catalytic processes. The system benefits from its simplicity due to increased substrate solubility, the possibility to conduct both reactions at their optimal temperatures and the elimination of isolating the reaction intermediate, which is prone to polymerization.

Statins, cholesterol-lowering drugs used for the treatment of coronary artery disease (CAD), are among the top 10 prescribed drugs worldwide. However, the synthesis of their characteristic side chain containing two chiral hydroxyl groups can be challenging. The application of deoxyribose-5-phosphate aldolase (DERA) is currently one of the most promising routes for the synthesis of this side chain. Herein, we describe the development of a continuous flow process for the biosynthesis of a side chain precursor. Design of experiments (DoE) was used to optimize the reaction conditions (pH value and temperature) in batch. A pH of 7.5 and a temperature of 32.5 °C were identified to be the optimal process settings within the reaction space considered. Additionally, an immobilization method was developed using the alginate-luffa matrix (ALM), which is a fast, simple, and inexpensive method for enzyme immobilization. Furthermore, it is non-toxic, biodegradable, and from renewable resources. The final continuous process was operated stable for 4 h and can produce up to 4.5 g of product per day.

The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical “Design of Experiments” (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield.