Optimization of a Catalytic Chemoenzymatic Tandem Reaction for the Synthesis of Natural Stilbenes in Continuous Flow

Abstract

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.

Expanding the Synthetic Toolbox through Metal–Enzyme Cascade Reactions

“…Some months later, the same authors reported the use of a 3D printed continuous stirred tank reactor that allowed an increase in the substrate concentration, and therefore of the productivity since the overall conversion was around 15% for the same reaction . Fine-tuning of the reaction conditions of the original report, and extension to other iodoaryl substrates allowed the synthesis of different stilbenes in 32–54% conversion under similar conditions …”

Chemoenzymatic approaches to plant natural product inspired compounds

“…Decarboxylation by encapsulated B. subtilis phenolic acid decarboxylase (PAD) was followed by a Heck coupling of the resultant vinylphenol to an aryl iodide. Resveratrol and methoxy- and dehydroxylated analogues 48 could be generated in 33–62% yield on a 1 mol scale in just 1 h. 55 …”

Continuous-Flow Synthesis of Arylthio-Cyclopropyl Carbonyl Compounds

“…The output was connected to a collection bottle, as shown in Scheme 1. Columns with the same internal diameter and different lengths (2, 10, 15 cm) were also filled with AR-35, following the same procedure described above, and studied in subsequent tests [42,43] (Figure 3). Initially, 1.0 M solutions of HCB 1a (20 mL) and 1.0 M thiol 2a (20 mL) were fluxed with high flow rates, resulting in low conversions of the corresponding adduct 3a (entry 1), Table 2.…”