Studies On The Asymmetric Total Synthesis Of (+)-Harringtonolide

The cage-like diterpenoid natural product?+?-harringtonolide contains a tropone ring,a cis-fused 5/6/6 tricyclic ring system carrying seven contiguous stereogenic centers,a bridged lactone,and a tetrahydrofuran ring.?+?-Harringtonolide was shown to inhibit the growth of tobacco and beans and to be antineoplastically and antivirally active;in addition,it was found to have potent cytotoxic activities with IC₅₀ = 43 nM for KB tumor cells.The intriguing architecture and outstanding biological activities,has rendered harringtonolide as extremely attractive target for synthetic studies.We envisioned that the 6-6 cis-fused rings could be constructed through an intramolecular Diels-Alder reaction,and the 5/7/6/6 tetracyclic could be assembled through an intramolecular [3+2] cycloaddition catalyzed by Rh₂?OAc?₄.Finally,the tropone ring,the bridged lactone and the ether ring moieties could be achieved by a sequence of late-stage functionalization from the oxapentacyclic derivative.According to the strategy,it was difficult to construct cage-like structure of the natural product after the 5/7/6/6 tetracyclic skeleton was achieved.Preliminary studies suggested that the carbon-carbon double bond on the six ring should be converted prior to the cycloaddition into a chlorohydrin moiety,which could be used to construct the lactone and THF rings at a late stage.X-ray diffraction shown us the relative stereochemistry of the C-OH and C-Cl,indicating that the ether and the lactone could be furnished successively.Gratifyingly,the tropone unit was smoothly constructed and the natural product was obtained upon treatment with Me₂AlCl when the carbonyl group within the seven-membered ring was converted into an enol ether to activate the C-H bond.An asymmetric transfer hydrogenation gave a chiral compound and the first enantioselective total synthesis of?+?-harringtonolide was realized following the successful route.