Structural Revision and Total Synthesis of Primarolides A and B via Massarinin A as a Common Precursor – Discovery of a Surprising 1,4‐Aryl Shift

To probe the possible non-enzymatic formation of the polyketidic fungal metabolites primarolides A and B, the supposed 2-formyl-benzophenone precursor was prepared by chemical synthesis exploiting an anionic homo-Fries rearrangement to set up the highly substituted benzophenone unit. Conversion of this compound into the putative primarolides (i. e. the isomeric phthalide and the corresponding N-phenyl-isoindolinone) revealed that the proposed structures had to be revised. Subsequently, the natural product massarinin A, which displays a similar 2-formyl-benzophenone substructure, was synthesized following a related strategy. Treatment of massarinin A with Sc(OTf)₃ or cyanide as a nucleophilic catalyst unexpectedly proceeded under 1,4-aryl migration to afford primarolide A. In contrast, reaction of massarinin A with aniline gave rise to primarolide B without aryl shift. All structural assignments were confirmed by X-ray crystal analysis and the proposed mechanism of the skeletal rearrangement was supported by ¹³C labeling. The study not only led to the total synthesis and structural revision of the primarolides but also supports the hypothesis of their non-enzymatic formation as racemates under the reported fermentation conditions, with the added suberoylanilide hydroxamic acid (SAHA) likely serving as the source of aniline.