N‐Heterocyclic Carbene‐Catalyzed Hauser–Kraus Annulation with 1,3‐Cyclopentenediones: Formal Total Synthesis of Fredericamycin A

Fredericamycin A (FDM‐A) has garnered significant interest from the synthetic community due to its fascinating chemical structure and notable antitumor activity since its first isolation in 1981. Herein, we developed an N‐heterocyclic carbene‐catalyzed hydroquinone formation reaction. The methyl ortho ‐formylbenzoate was used as a starting material and reacted with the cyclopentene‐1,3‐diones to afford the desired hydroquinone products in good yields. The reaction undergoes in mild conditions at room temperature, making the reaction system well‐tolerated for many functional groups. Furthermore, the enantioselective variant of this hydroquinone formation was realized with a chiral NHC precatalyst, affording the product with moderate enantioselectivity. With the help of our method, the synthesis of FDM‐A was achieved. Moreover, several analogs of FDM‐A are readily available as well. Preliminary cytotoxicity evaluation revealed that these analogs exhibited moderate to weak inhibitory activity against CCRF‐CEM cells.