In Situ Acetaldehyde Synthesis for Carboligation Reactions

The enzyme 4‐oxalocrotonate tautomerase (4‐OT) can promiscuously catalyze various carboligation reactions using acetaldehyde as a nucleophile. However, the highly reactive nature of acetaldehyde requires intricate handling, which can impede its usage in practical synthesis. Therefore, we investigated three enzymatic routes to synthesize acetaldehyde in situ in one‐pot cascade reactions with 4‐OT. Two routes afforded practical acetaldehyde concentrations, using an environmental pollutant, trans‐3‐chloroacrylic acid, or a bio‐renewable, ethanol, as starting substrate. These routes can be combined with 4‐OT catalyzed Michael‐type additions and aldol condensations in one pot. This modular systems biocatalysis methodology provides a stepping stone towards the development of larger artificial metabolic networks for the practical synthesis of important chemical synthons.