Total Synthesis Confirms Laetirobin as a Formal Diels–Alder Adduct

Laetirobin, isolated from a parasitic fungus host–plant relationship, was synthesized in six practical steps with an overall yield of 12 % from commercially available 2,4‐dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)‐mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem‐diaryl alkene precursors. Preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).