Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Total Synthesis

Monday, April 7, 2014
Douglass F. Taber
University of Delaware

The Njardarson Synthesis of Vinigrol

The diterpene vinigrol 3, isolated from Virgaria nigra F-5408, is a tumor necrosis factor (TNF) inhibitor. Jon T. Njardarson of the University of Arizona envisioned (Angewandte Chem. Int. Ed. 2013, 52, 8648. ) that Wharton fragmentation of 1 could deliver 2, suitably functionalized for elaboration to 3.

The tetracyclic 1 was prepared by the triply-convergent assembly of the phenol 11. Addition of allyl magnesium bromide to 4 proceeded with high regio- and geometric selectivity, to gave an alcohol that was methylated, then iodinated with inversion to give 5. Condensation of the phosphonate with the derived aldehyde 6 led to the alcohol 8, that was coupled under Mitsunobu conditions with the phenol 9 to give 10. Oxidation of 11 gave an intermediate that underwent intramolecular Diels-Alder cycloaddition to deliver 12. On exposure to Pd catalyst 12 cyclized to the diene 13.

On exposure to tBuOK/tBuOH, the mesylate 1 smoothly fragmented to the hoped-for ketone 2. Although this has been referred to as a Grob fragmentation, in fact this reaction was developed (J. Org. Chem. 1961, 26, 4781. ) by Peter S. Wharton, then at the University of Wisconsin, and would more properly bear his name.

Subsequent transformations took advantage of the hindered nature of the trisubstituted alkene of 2. Hydrogenation of the disubstituted alkene proceeded selectively, to give an intermediate that was condensed with 14, leading to the enone 15. Two more selective hydrogenations, with the Wittig methylenation in between, completed the construction of the pendant isopropyl group.

Once the isopropyl group was installed, what remained was the oxidation of 16 to 19. The epoxidation of 17 proceeded with high facial selectivity, to give an intermediate that was carried on by iodination and reduction to the alcohol 18. Allylic oxidation converted 18 into 19, that was deprotected to give Vinigrol 3.

It is instructive to compare and contrast this approach to vinigrol (3) with the two that we have previously highlighted (The Baran Synthesis of Vinigrol 2010, September 6; Diels-Alder Cycloaddition: Fawcettimine (Williams), Apiosporic Acid (Helmchen), Marginatone (Abad-Somovilla), Okilactomycin (Hoye), Vinigrol (Barriault), Plakotenin (Bihlmeier/Klopper) 2012, December 24) Each strategy offers its own advantages.

D. F. Taber, Org. Chem. Highlights 2014, April 7.