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 CO ether bonds to be performed under mild and sustainable conditions are highly desired. Here we present a biocatalytic shuttle concept making use of corrinoiddependent 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.

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.

A biocatalytic system is presented for the stereoselective amination of ketones at the expense of NH3 and molecular hydrogen. By using a NAD(+)-reducing hydrogenase, an alanine dehydrogenase, and a suitable ω-transaminase, the R- as well as the S-enantiomer of various amines could be prepared with up to >99% ee and 98% conversion.

Isomerization is a fundamental reaction in chemistry. However, isomerization of phenyl methyl ethers has not been described yet. Using a cobalamin-dependent methyl transferase, a reversible shuttle concept was investigated for isomerization of catechol monomethyl ethers. The methyl ether of substituted catechol derivatives was successfully transferred onto the adjacent hydroxy moiety. For instance, the cobalamin-dependent biocatalyst transformed isovanillin to its regioisomer vanillin with significant regioisomeric excess (68% vanillin). To the best of our knowledge, isomerization by methyl transfer employing a methyl transferase has not been reported before.

Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing, is a preferred way for the production of customized reactors. This work presents three examples of 3D printed reactors and their application for the synthesis of API precursors in continuous flow. The first case deals with an aerobic oxidation of Grignard reagents to the corresponding phenols by molecular oxygen. Here, a design concept was utilized; various stainless steel reactors were tested, and their performances were evaluated in continuous flow. Next, another stainless steel reactor was applied for achieving fast mixing in a cascade, leading to a valsartan precursor. The third and final case employed a continuous stirred tank reactor (CSTR) made of a UV-curable resin. It was used for the first step of a multiphase enzymatic decarboxylation followed by a Heck cross-coupling reaction, leading to resveratrol derivatives.

Waterborne polyurethane dispersions (PUDs) have gained significant importance in the coating industry due to their diverse chemical and physical properties. However, a comprehensive analysis of their environmental impacts is lacking. Therefore, this study provides a comparative life cycle assessment (LCA) of four different PUD production processes from cradle-to-gate. The environmental performances of the NMP process, the acetone process, the melt process, and a conceptualized continuous flow process were evaluated and compared following the CML 2001 methodology. The LCA revealed that the conceptualized flow process exhibits the lowest environmental impact in all investigated impact categories. Depending on the impact category, the melt process or the acetone process rank second. The NMP process was observed to have the highest impact in all categories. Consequently, the flow process has the lowest carbon footprint (1.13 kg CO 2eq), according to the global warming potential (100 years), followed by the melt (1.45 kg CO 2 -eq), the acetone (1.95 kg CO 2 -eq), and the NMP process (3.11 kg CO 2 -eq).

Valsartan is a potent, orally active angiotensin II receptor blocker and is widely used in the treatment of hypertension and chronic heart failure. Herein, we present an approach for the continuous synthesis of a late-stage precursor of valsartan in three steps. The applied synthetic route involves N-acylation, Suzuki-Miyaura cross-coupling and methyl ester hydrolysis. After optimization of the individual steps in batch, they were successfully transferred to continuous flow processes employing different reactor designs. The first step of the synthetic route (N-acylation) as well as the third step (methyl ester hydrolysis) are performed in coil reactor setups. The key step of the reaction cascade (Suzuki-Miyaura cross-coupling) is catalyzed by a heterogeneous palladiumsubstituted cerium-tin-oxide with the molecular formula Ce 0.20 Sn 0.79 Pd 0.01 O 2-δ. The catalyst particles are implemented in an in-house developed packed-bed reactor, which features an HPLC column as fixed-bed. The combination of the individual reaction modules facilitates the consecutive performance of the three reaction steps. Using the developed multistep continuous setup, the targeted valsartan precursor was obtained with up to 96% overall yield.

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.