Biomimetic Synthesis of Seven Halenaquinone Meroterpenoids

Structurally similar natural products arising in phylogenetically distant organisms may reflect convergent evolutionary pressure toward privileged biological scaffolds. The marine sponge-derived halenaquinone meroterpenoids exemplify this phenomenon, sharing a highly electrophilic and strained diketofuran motif with both the viridin/wortmannin and hibiscone families of natural products. Guided by biosynthetic reasoning, we report herein a biomimetic route to the halenaquinone family. Central to the strategy is an aryne-furan Diels-Alder reaction that rapidly constructs the tetracyclic carbon framework, together with oxidative decarboxylation of a diosphenol intermediate, followed by divergent late-stage oxidative cyclizations to furnish either xestoquinone or halenaquinone. This platform enabled the synthesis of seven natural products, three structural revisions, and the discovery of potent cytotoxic activity for several family members.