A heterogeneous chemoenzymatic route toward the continuous transformation of γ-alkynoic acids into γ-hydroxy acids

The combination of chemocatalysts and biocatalysts enables access to synthetic routes that would otherwise be elusive when using either catalyst type in isolation. However, most chemoenzymatic routes have been limited due to incompatibility issues. Catalyst compartmentalization is an effective strategy to overcome these issues. In this work, we demonstrate the heterogenization of a Au catalyst and the versatile ketoreductase from Lactobacillus kefir to perform a model three-step chemoenzymatic cascade that continuously transforms 4-pentynoic acid into 4-(R)-hydroxypentanoic acid with exquisite enantioselectivity. To this aim, we telescope two packed-bed reactors that physically segregate a chemoenzymatic cycloisomerization/hydrolysis step from the self-sufficient biocatalytic asymmetric reduction. As a result, the chemoenzymatic system continuously operated at pH 3.8 maintains a constant space-time yield (STY) of 0.47 g L−1 h−1 for 24 h, highlighting the excellent operational stability of the catalysts. Overall, our findings emphasize the importance of catalyst spatial orchestration to develop efficient hybrid chemoenzymatic cascades.