Enantioselective Total Synthesis of (+)-Garsubellin A

Angew Chem Int Ed Engl. 2021 Oct 11;60(42):22735-22739. doi: 10.1002/anie.202109193. Epub 2021 Sep 9.

Abstract

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)-garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2-ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve-step, protecting group-free synthetic route has enabled the syntheses of both the natural (-)-garsubellin A and its unnatural (+)-antipode for biological evaluations.

Keywords: PPAP; carbocycles; carbonylation; natural products; total synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Bridged Bicyclo Compounds / chemistry
  • Crystallography, X-Ray
  • Cyclization
  • Molecular Conformation
  • Stereoisomerism
  • Terpenes / chemical synthesis*
  • Terpenes / chemistry

Substances

  • Biological Products
  • Bridged Bicyclo Compounds
  • Terpenes
  • garsubellin A