Total synthesis of (±)-hippolachnin A and progress toward the total synthesis of (±)-citrinadin A.


In 2005, Kobayashi and coworkers reported the isolation and characterization of the alkaloid natural product citrinadin A from the marine fungus Penicillium citrinum. Citrinadin A was found to exhibit modest cytotoxicity against cancer cell lines, and possesses an intriguing molecular architecture that has made it a fascinating target for total synthesis. Our approach to the core of this compound features an unusual (2+3) nitrone cycloaddition that affords a highly convergent synthetic approach, and has resulted in the synthesis of a highly advanced synthetic intermediate. However, the enticing nature of citrinadin A led our efforts to be precluded by those of a competing laboratory and we ultimately ceased our synthetic studies toward this molecule. The marine natural product hippolachnin A was isolated from the sponge Hippospongia lachne in 2013 and found to exhibit potent anti-fungal activity against Cryptococcus neoformans – the leading cause of fungal meningitis and a clinically unmet need in modern mycology. In addition to its biological activity, hippolachnin A possesses a previously unknown structure and presents a highly challenging synthetic target. Our approach to this molecule employs an unprecedented Lewis acid promoted [2π+2σ+2σ] cycloaddition between the unusual and highly strained alkane quadricyclane and an electron deficient olefin. This reaction rapidly assembles the core of the molecule, and enables a novel late stage C-H oxidation in the final stages of the synthesis. This route was completed in nine steps from known materials, and was ultimately combined with a competing route to give hippolachnin A in six steps from quadricyclane in the first collaborative total synthesis to date.



Citrinadin A. Citrinadin B. Hippolachnin A. Total synthesis. Natural products. Quadricyclane. Dipolar. Cycloaddition. C-H activation. C-H oxidation.