The First Total Synthesis Of(+)-plumisclerin A

Plumisclerin A is a unique cytotoxic marine diterpenoid having a novel skeleton of terpene,plumisclerane.It contains a congested,high-strained tricycle[4.3.1.01,5]decane skeleton,and its dihydropyran ring is trans-fused to the tricyclic decane system,making the molecular tension to be further serious.In addition,its absolute configuration remains ambiguous yet.This compound displayed moderate cytotoxic activity against several tumor cells.Obviously,plumisclerin A is an attractive and valuable marine natural product target both in academic and pharmaceutical research.Our previous work developed a SmI2-mediated ketyl radical conjugate addition,which was applied to construction of the tricycle[4.3.1.01,5]decane framework successfully.In this thesis,around the central cyclopentane anchorage,a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5]decane and trans-fused dihydropyran moiety.A La-catalyzed enantioselective Michael reaction,an intramolecular aldol condensation,a Pd-catalyzed carbonylation and a SmI2-mediated radical conjugate addition successfully and efficiently served as the key operations in multigram-scale construction of the enantiopure rigid B/C/D-ring system bearing six continuous stereogenic centers including two all-carbon quaternary carbons.Construction of the trans-fused dihydropyran ring in one step was turned out to be difficult neither by intramolecular condensation of two aldehyde groups or by intramolecular cycloisomerization of alkynyl alcohol/alkynadehyde substrates.To overcome the above problem,a stepwise synthesis was adopted applying a Claisen condensation to introduce the branching units and internal lactonization to construct the trans-fused lactone ring.Redox modification of the lactone moiety finally delivered the completion of the first total synthesis of plumisclerin A and clear assignment of its absolute configuration as(IR 4aS,6S,7R,11S,11aR,12S).It's noteworthy that the disclosed total synthesis is also the first example of total synthesis for plumisclerane diterpenoids.