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Organic Chemistry Highlights

Total Synthesis

Monday, September 6, 2010
Douglass F. Taber
University of Delaware

The Baran Synthesis of Vinigrol

The diterpene vinigrol (3), isolated from Virgaria nigra F-5408, has eluded total synthesis for more than twenty years. Attempts to construct the four-carbon bridge on a preformed cis-decalin have been unavailing. Phil S. Baran of Scripps/LaJolla solved (Angew. Chem. Int. Ed. 2008, 47, 3054, DOI: 10.1002/anie.200800167; J. Am. Chem. Soc. 2009, 131, 17066, DOI: 10.1021/ja908194b) this problem by adding the extra C-C bond of 1, that could then be cleaved in course of a Grob fragmentation, leading to 2.

The preparation of 1 started with the dihydroresorcinol derivative 4. Diels-Alder addition of the ester 5 gave 6, with a modest 2:1 dr. Addition of allyl magnesium chloride to the derived aldehyde 7 proceeded with 6:1 dr. The resulting triene was conformationally sufficiently constrained that cyclization to 8 proceeded at room temperature over two weeks, or more conveniently at 105C for 90 minutes. With 8 in hand, oxidation to the ketone allowed installation of the additional methyl group of 9. Desilylation followed by OH-directed reduction set the relative configuration of 1 correctly for the Grob fragmentation to the Z-alkene 2.

There were two remaining problems in the synthesis. The alkene of 2 had to be converted to the methylated tertiary alcohol, and the ketone had to be elaborated to the ene diol. While seemingly straightforward, the congested tricyclic skeleton of 2 made many common transformations difficult. The solution to the former problem was found in the selective dipolar addition of bromonitrile oxide. Reduction of the ketone then enabled HO-directed hydrogenation of the alkene, that otherwise was resistant. Dehydration followed by reduction with LiAlH4 gave the desired methyl group bearing a primary amine, that was removed by free radical reduction of the corresponding isonitrile, to give 12.

With 12 in hand, the end of the synthesis appeared to be in sight. In fact, the reduction of a variety of oxidized intermediates proved difficult. In the end, a sequence that did not require reduction proved effective. Dihydroxylation of 12 gave a diol, selective oxidation of which delivered the α-hydroxy ketone 13. Formation of the trisylhydrazone followed by Shapiro reaction gave the intermediate alkenyl anion, that was trapped with formaldehyde to give the long-sought Vinigrol (3).

Vinigrol (3) produced by this sequence was racemic. The absolute configuration of the ring system was set in the course of the Diels-Alder addition of 5 to 4. Use of a chiral catalyst in this step could set the stage for an enantioselective synthesis of 3.

D. F. Taber, Org. Chem. Highlights 2010, September 6.