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

In the field of biocatalysis, discovering novel reactivity from known enzymes has been a longstanding challenge. Fatty acid photo-decarboxylase from Chlorella variabilis (CvFAP) 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 CvFAP 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 CvFAP promiscuity, and thus expands the reactivity repertoire of CvFAP and highlights the versatility of CvFAP in asymmetric synthesis.