Synthetically established methods for methylation of phenols and demethylation of methyl phenyl ethers rely in general on hazardous reagents or/and harsh reaction conditions and are irreversible. Consequently, alternative regioselective methods for the reversible formation and breakage of C-O-ether bonds to be performed under mild and sustainable conditions are highly desired. Here we present a biocatalytic shuttle concept making use of corrinoid-dependent methyl transferases from anaerobic bacteria. The two-component enzymatic system consists of a corrinoid protein carrying the cofactor and acting as methyl group shuttle, and a methyltransferase catalyzing both methylation and demethylation in a reversible fashion. Various phenyl methyl ethers are successfully demethylated and serve in addition as sustainable methylating agents for the functionalization of various substituted catechols. Therefore, this methyl transfer approach represents a promising alternative to common chemical protocols and a valuable add-on for the toolbox of available biocatalysts.

In view of the development of efficient processes for the synthesis of high-value compounds, the combination of bio- and chemocatalysis is highly promising. In addition, implementation of immobilized catalysts into continuous setups allows a straightforward separation of the target compound from the reaction mixture and ensures uniform product quality. In this work, we report the optimization of a chemoenzymatic tandem reaction in continuous flow and its extended application for the synthesis of pharmacologically active resveratrol and pterostilbene. The tandem reaction involves enzymatic decarboxylation of coumaric acid employing encapsulated phenolic acid decarboxylase from B. subtilis and a Heck coupling of the obtained vinylphenol with an aryl iodide using heterogeneous Pd-Ce-Sn oxides implemented in a packed bed reactor. By optimization of the reaction conditions for the limiting cross-coupling step, the yield of (E)-4-hydroxystilbene using the fully continuous setup could be more than doubled compared to previous work. Furthermore, the improved chemoenzymatic cascade could also be applied to the synthesis of resveratrol and pterostilbene in a continuous fashion. Leaching of the metal catalyst at high temperatures limited the process in many perspectives. Therefore, the feasibility of a reactor setup with reversed flow was experimentally evaluated and approved.

Within the “compartmentalised smart factory” approach of the ONE-FLOW project the implementation of different catalysts in “compartments” provided by Pickering emulsions and their application in continuous flow is targeted. We present here the development of heterogeneous Pd catalysts that are ready to be used in combination with biocatalysts for catalytic cascade synthesis of active pharmaceutical ingredients (APIs). In particular, we focus on the application of the catalytic systems for Suzuki–Miyaura cross-coupling reactions, which is the key step in the synthesis of the targeted APIs valsartan and sacubitril. An immobilised enzyme will accomplish the final product formation via hydrolysis. In order to create a large interfacial area for the catalytic reactions and to keep the reagents separated until required, the catalyst particles are used to stabilise Pickering emulsions of oil and water. A set of Ce–Sn–Pd oxides with the molecular formula Ce_0.99−xSn_xPd_0.01O_2−δ (x = 0–0.99) has been prepared utilising a simple single-step solution combustion method. The high applicability of the catalysts for different functional groups and their minimal leaching behaviour is demonstrated with various Suzuki–Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called “plug & play reactor”. Finally, we demonstrate the use of these particles as the sole emulsifier of oil–water emulsions for a range of oils.

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.