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 Alzheimers 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 twelvestep, protecting group-free synthetic route has enabled the syntheses of both the natural (À)-garsubellin A and its unnatural (+)-antipode for biological evaluations.Scheme 1. Structure and retrosynthesis of Garsubellin A.
Garsubellin A is a thirty‐carbon meroterpenoid capable of enhancing the enzyme choline acetyltransferase whose decreased level is associated with the symptoms of Alzheimer's disease. Due to the potentially useful biological activity along with the novel molecular architecture, this plant metabolite has remained a popular synthetic target. Herein we report a full account of our synthetic investigations that have led to the enantioselective total synthesis of garsubellin A, establishing its absolute stereostructure. The protecting group‐free, twelve‐step synthetic route has enabled the syntheses of the natural (−)‐garsubellin A and its unnatural (+)‐antipode.
Dedicated to Prof. E. Peter Kündig on the occasion of his 75th birthday and retirementDescribed here is the rhodium(I)-catalyzed tandem addition-cyclization of 1,5-enynes with aryl-and alkenylboronic acids. In the presence of triethylamine and catalytic [Rh(OH)(COD)] 2 in methanol, both the terminal and internal alkyne substrates possessing an electron-deficient alkene undergo inter-and intramolecular CÀ C bond formations to yield alkylidene -cyclobutane products. The reaction proceeds through a series of processes involving generation of an aryl or alkenyl rhodium from the organoboronic acid, 1,2-syncarbometalation of the alkyne and 4-exo-type-cyclization of the resulting alkenyl rhodium intermediate with the tethered, carbonyl-conjugated alkene. Thus, the reaction enables a net R,H-addition across the 1,5-enyne πsystem -hydroarylation and hydroalkenylation -under mild rhodium catalysis while achieving 4-membered ring formation. Preliminary studies show that the reaction can also be rendered enantioselective by employing a chiral diene ligand for the rhodium catalyst.
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 Alzheimers 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 twelvestep, protecting group-free synthetic route has enabled the syntheses of both the natural (À)-garsubellin A and its unnatural (+)-antipode for biological evaluations.Scheme 1. Structure and retrosynthesis of Garsubellin A.
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