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

Abstract

Constructing a nearly symmetrical chiral center with tiny chiral differences is a challenging task in asymmetric synthesis. The natural antibiotic fredericamycin A (FDM-A), a representative example, has a unique structure with a quasi-symmetrical spirocyclic hydroquinone and remains difficult to chemically synthesize. 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. Using our method, the asymmetric synthesis of FDM-A (previously requiring a 26-step or 32-step synthesis) was shortened to 11 steps. Several analogs of FDM-A were also readily made. Moreover, a more challenging all-carbon quaternary chiral center with minimal differences (H vs. D) in a remote position (6 atoms away from the chiral center) was also constructed to investigate the performance of the extremely weakly chiral small molecule.