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Organic Chemistry Highlights

Total Synthesis

Monday, December 7, 2009
Douglass F. Taber
University of Delaware

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

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. DOI: 10.1021/ja9019484) 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 with the diazo ester 5. Though closely related to the α-diazo β-keto ester 6, the alkene of 5 donates electron density to the intermediate Rh carbene, making it more susceptible to the influence of the chiral ligands. The alkene of the enol ether then participated in the Cope rearrangement, delivering 8. Routine functional group transformation then converted 8 to 1, that cyclized smoothly to 2.

The enol ether of 2 was reduced with high diastereocontrol to give 10. The ketone was installed by allylic oxidation, setting the stage for attachment of the two pendant sidechains of 3 by conjugate addition followed by enolate trapping. Cu-catalyzed addition of the α-oxygenated organolithium 12 proceeded well in the presence of TMS-Cl, to establish the silyl enol ether 13. Allylation of the regenerated enolate proceeded at oxygen, but the enol ether 14 so prepared rearranged to the desired C-alkylated product 15 on microwave heating.

The synthesis endgame was based on an unusual transformation, the addition to the keto aldehyde 16 of the phosphonium salt 17, developed (Tetrahedron 2008, 64, 6482. DOI: 10.1016/j.tet.2008.04.068) by the Williams 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 ring construction developed by the Davies group. The Williams phosphonium salt will also have general applicability. In a simpler manifestation, conversion of an aldehyde to, e.g., the enol benzoate, followed by exposure to dilute methoxide, will allow the conversion of an aldehyde to the aldehyde one carbon longer, without the acidic hydrolysis usually required for such a transformation.

D. F. Taber, Org. Chem. Highlights 2009, December 7.