Enantioselective Total Synthesis of (+)-Plumisclerin A

Abstract

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5 ]decane and trans-fused dihyrdopyran moiety. Scalable enantioselective La^III -catalyzed Michael reaction, palladium(0)-catalyzed carbonylation and SmI₂ -mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D-ring system having six continuous stereogenic centers and two all-carbon quaternary centers. The trans-fused dihyrdopyran moiety with an exo side-chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)-plumisclerin A.

Keywords: conjugate addition; enantioselective synthesis; plumisclerin A; samarium diiodide; total synthesis.