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
Year: 2025
Type: article
Abstract: 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 13 C 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.
Source: Chemistry - A European Journal
Authors: Marvin Schwamborn, Linus Stremmel, Jörg‐Martin Neudörfl, Hans‐Günther Schmalz
Institution: University of Cologne
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,640
OpenAlex ID: W4407222942