Catalytic Promiscuity of Fatty Acid Photodecarboxylase Enables Stereoselective Synthesis of Chiral α‐Tetralones

Abstract In the field of biocatalysis, discovering novel reactivity from known enzymes has been a longstanding challenge. Fatty acid photo‐decarboxylase from Chlorella variabilis ( Cv FAP) has drawn considerable attention as a promising photoenzyme with potential green chemistry applications; however, its non‐natural reactivity has rarely been exploited to date. Herein we report a non‐natural reductive dehalogenation (deacetoxylation) reactivity of Cv FAP inspired by its natural oxidative decarboxylation process, enabling the stereoselective synthesis of a series of chiral α‐substituted tetralones with high yields (up to 99 %) and e.r. values (up to 99 : 1). Mechanistic studies demonstrated that the native photoenzyme catalyzed the reductive dehalogenation via a novel mechanism involving oxidized state (FAD ox )/semiquinone state (FAD sq ) redox pair and an electron transfer (ET)/proton transfer (PT) process of radical termination, distinct from the previous reports. To our knowledge, this study represents a new example of Cv FAP promiscuity, and thus expands the reactivity repertoire of Cv FAP and highlights the versatility of Cv FAP in asymmetric synthesis.