The Davies / Williams Synthesis of (-)-5- epi -Vibsanin E

Abstract

There are currently 61 known vibsane-type diterpenes, as exemplified by (-)-5-epi –Vibsanin E 3. The first synthesis of 3, described (J. Am. Chem. Soc. 2009, 131, 8329) by Huw M. L. Davies of Emory University and Craig M. Williams of the University of Queensland, was based on the enantioselective seven-membered ring construction developed by the Davies group and the end game established by the Williams group. A key step in the synthesis was the intramolecular hetero Diels-Alder cyclization of 1 to 2.The absolute configuration of 1 was set by the Rh-mediated cyclopropanation of 4 withthe diazo ester 5. Though closely related to the α-diazo β-keto ester 6, the alkene of 5donates electron density to the intermediate Rh carbene, making it more susceptible tothe influence of the chiral ligands. The alkene of the enol ether then participated in theCope rearrangement, delivering 8. Routine functional group transformation then converted8 to 1, that cyclized smoothly to 2.The enol ether of 2 was reduced with high diastereocontrol to give 10. The ketone wasinstalled by allylic oxidation, setting the stage for attachment of the two pendant sidechainsof 3 by conjugate addition followed by enolate trapping. Cu-catalyzed addition of theα-oxygenated organolithium12 proceeded well in the presence of TMS-Cl, to establish thesilyl enol ether 13. Allylation of the regenerated enolate proceeded at oxygen, but the enolether 14 so prepared rearranged to the desired C-alkylated product 15 on microwaveheating.The synthesis endgame was based on an unusual transformation, the addition to the ketoaldehyde 16 of the phosphonium salt 17, developed ( Tetrahedron 2008 , 64 , 6482) by theWilliams group. This allowed the introduction of the complete vinyl ester array of (-)-5-epi-Vibsanin E 3.This synthesis illustrates the power of the elegant enantioselective seven-membered ringconstruction developed by the Davies group. The Williams phosphonium salt will also havegeneral applicability.