Visible-Light-Mediated Site-Selective C(sp2)–H Alkylation of Tropones Enables Semi-Synthesis of Cephafortunoids A and B and a Reconsideration of Their Biosynthesis

The synthesis of functionalized tropones constitutes an underexplored chemical space, primarily due to the intrinsic structural properties of the aromatic nucleus. This predicament has impeded extensive investigation into their potential applications in organic and medicinal chemistry. Here, we report a mild and straightforward visible-light-mediated protocol for the α-site-selective C(sp2)–H alkylation of tropones, employing unactivated secondary amines as alkylating agents. This method yields up to 88% in 41 examples, and is significantly amenable to late-stage functionalization. The utility is showcased by the effective chemical trasformation of fortunolide A to cephafortunoids A and B, representing the first synthetic entry to this unique class of C20 Cephalotaxus troponoids. Significantly, this achievement reinforces the chemical feasibility of the newly hypothesized biosynthesis involving direct methylation catalyzed by S-adenosylmethionine (SAM).