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Totally Synthetic by Paul H. Docherty, 28 January 2008

Total Synthesis of Vigulariol


J. Becker, K. Bergander, R. Fröhlich, D. Hoppe, Angew. Chem. Int. Ed. 2008, 1654-1657.

DOI: 10.1002/anie.200704678

Vigulariol was covered a year ago, with a nice racemic synthesis by Steve Clark. However, a recent asymmetric synthesis by Dieter Hoppe was brought to my attention featuring a very interesting domino reaction!

The natural product is a cytotoxic marine diterpene of the cladiellin (eunicellin) family. However, the cyctoxicity isn’t particularly potent, so let’s focus on the chemical structure:

The synthesis effectively stems from a three-component coupling, in which each component is the product of a short synthesis. For example, the central cyclohexene fragment could be derived from a component of commercial eucalyptus oil in seven steps.

The coupling starts with a substrate directed deprotonation of the cyclohexenol. The carbamate moiety ligates the lithium, which is also chelated to by the trans-tetramethyl-1,2-diaminocyclohexane. They then add Ti(IV), which performs a metal exchange followed by an aldol reaction with the aldehyde fragment, returning a reasonable 83:17 d.r. The mixture of diastereoisomers was then treated with a Lewis acid to promote the condensation onto the third fragment, the diethyl acetal. This set two further stereocenters with apparent complete control. A very interesting step!

They finished the synthesis with only another four steps. A key RCM reaction constructed the nine-member ring - several other groups working on this type of natural product have serious problems with RCM. Their RCM went in reasonable 45%, but also yielding an eight-member ring analogue with an exo-methylene group. The following substrate controlled epoxidation with DMDO went in good yield, preparing them for the last cyclisation.

Removal of the benzyl protecting group, followed by the formation of the tetrahydrofuran ring completed the carbocyclic skeleton of the natural product. A Wittig methylenation of the ketone finished the total synthesis. Although the yields for the shown reactions aren’t fantastic, that strategy for the total synthesis of this complex target is incredible.