Enantioselective Total Synthesis of Berkeleyone A and Preaustinoids

Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (-)-berkeleyone A and its five congeners ((-)-preaustinoids A, A1, B, B1, and B2) in 12-15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)(3)-mediated sequential Krapcho dealkoxycarbonylation/carbonyl alpha-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (alpha-ketol, alpha-hydroxyl-beta-diketone, etc.) responsible for the biomimetic diversification of (-)-berkeleyone A into its five preaustinoid congeners.

Automated summary

In this report, the first enantioselective total synthesis of (-)-berkeleyone A and its five congeners is presented, achieved in 12-15 steps starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. The synthesis features symmetry-breaking reactions and complex framework formation, while biomimetic investigations revealed rearrangements responsible for the diversification of (-)-berkeleyone A into its congeners.