Carbene-catalyzed enantioselective construction of quasi-symmetrical spirocyclic hydroquinone with minor chiral distinction

Constructing nearly symmetrical chiral center with tiny chiral differences is a challenging task in asymmetric synthesis. As a representative example, natural antibiotic Fredericamycin A (FDM-A) has a unique structure with quasi-symmetrical spirocyclic hydroquinone and remains difficult for chemical synthesis. Herein we developed an N-heterocyclic carbene-catalyzed enantioselective hydroquinone formation reaction, with desymmetrization of spirocyclic cyclopentene-1,3-diones to construct these challenging structures. With the help of our method, the asymmetric synthesis of FDM-A (require 26-step or 32-step synthesis) was shortened to 11 steps. Several analogs of FDM-A are readily available as well. Moreover, a more challenging all-carbon quaternary chiral center with minimal differences (H vs. D) in remote position (6 atoms away from the chiral center) was also constructed to investigate the performance of the extremely weak-chirality small molecule.