Visible-light-mediated site-selective C(sp ² )–H alkylation of tropones facilitates semi-synthesis of cephafortunoids A and B

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 89% in 48 examples, and is significantly amenable to late-stage functionalization. The utility is showcased by the effective chemical transformation of fortunolide A into cephafortunoids A and B, representing the first synthetic entry to this unique class of C₂₀ <i>Cephalotaxus</i> troponoids. Significantly, this achievement reinforces the chemical feasibility of the newly hypothesized biosynthesis involving direct methylation <i>via</i> radical <i>S</i>-adenosylmethionine (SAM)-dependent methyltransferases.