AbstractA versatile and highly efficient three‐step, one‐pot, enzyme‐promoted Passerini tandem reaction has been developed. The chemoenzymatic sequence involved simultaneous enzyme catalyzed hydrolysis, subsequent Passerini reaction, and enzymatic kinetic resolution of the Passerini product. This methodology combines the diversity delivered by multicomponent reactions with the selectivity of biocatalysts, which results in efficient synthesis of the target compounds with excellent enantiomeric excesses of up to 99 %. With a small set of substrates, a large library of complex molecules was obtained within a short time by using the developed procedure.