The Plakotenins: Biomimetic Diels-Alder Reactions, Total Synthesis, Structural Investigations, and Chemical Biology

The total synthesis of plakotenin, a cytotoxic marine natural product, using a biomimetic Diels–Alder reaction is described in detail. Two approaches were used, whereby the Diels–Alder reaction occurs at different stages of the synthesis. Homo‐ and nor‐plakotenin, related natural products, were also prepared, as well as iso‐plakotenin, a diastereoisomer of plakotenin. The syntheses prove the relative and absolute stereochemistry of the latter. The chemical biology of the plakotenins was investigated on selected compounds. Plakotenins—the full family: The total syntheses of plakotenin, iso‐plakotenin, nor‐plakotenin, and homo‐plakotenin have been described using a “late‐stage” biomimetic ring closure and an “early‐stage” Diels–Alder reaction with subsequent modification (see scheme). Biological tests were investigated showing that the stereochemistry was an important aspect for cytotoxicity.