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Organic Chemistry Highlights

Total Synthesis

Monday, July 6, 2020
Douglass F. Taber
University of Delaware

The Li Synthesis of Vinigrol

Vinigrol (3), isolated from the fungus Virgaria nigra F-5408, is an antagonist of tumor necrosis factor (TNF-α). Chuang-Chuang Li of the Southern University of Science and Technology assembled the medium ring of 3 by the type II intramolecular [5+2] cycloaddition of 1 to 2 (J. Am. Chem. Soc. 2019, 141, 15773. DOI: 10.1021/jacs.9b08983)

The requisite side chain 7 for the preparation of 1 was constructed following the Boeckman protocol, using the Hayashi catalyst (5) to mediate the condensation of 4 with formaldehyde to give 6. The assembly of 7 was then completed by methylenation followed by an Appel bromination.

The starting material for the preparation of 2 was the carvone-derived allylic chloride 8. Deprotonation followed by the addition of 9 led to the ketone 10. Reduction and dehydration delivered the furan, that was coupled with 7 to give 11. Deprotonation followed by the addition of formaldehyde gave the intermediate primary alcohol, that was converted to 1 by Achmatowicz oxidation followed by combination with trifluoroethanol. Conversion to 12 followed by cyclization, in a reaction that could be carried out on a gram scale, proceeded smoothly to deliver 2.

With 2 in hand, the challenge was to remove the extra carbon in the ring. After hydrogenation to 13, it was observed that oxidation with excess IBX led to the α-hydroxy diketone 14. This could be rearranged to the isolable β-lactone 15. In practice, the oxidation to 14 was followed directly by further rearrangement, leading via retro [2+2] loss of CO2 to the ketone 16.

Reduction of 16 proceeded smoothly to give the ketone, that was acylated with Mander's reagent, then selenated, leading to 17. The synthesis of vinigrol 3 was completed by Dibal reduction followed by singlet oxygenation and reduction.

As always, it is instructive to compare this work to the five previous approaches that have been covered in these Highlights.

D. F. Taber, Org. Chem. Highlights 2020, July 6.