Directed Evolution of Artificial Enzyme with a Catalytic Noncanonical Amino Acid for Asymmetric Friedel–Crafts Alkylation of Cyclic Enones with Indoles

Abstract Direct activation of α,β-unsaturated ketones for enantioselective transformations has remained rare to enzyme catalysis due to their lower electrophilicity and challenging steric environment. In this work, we establish an enantioselective Friedel–Crafts alkylation of α,β-unsaturated cyclic ketones with indoles using a fully genetically encoded artificial enzyme featuring a catalytic primary amine residue. This abiological catalytic center enables iminium ion formation with cyclic enones, thereby unlocking a new reaction manifold for biocatalysis. This study offers a versatile platform for enantioselective transformations of α,β-unsaturated ketones, advancing the integration of new-to-nature catalysis into biocatalytic synthesis.