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Totally Synthetic by Paul H. Docherty, 10 August 2009

Total Synthesis of Dioxepandehydrothyrsiferol


J. Tanuwidjaja, S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc. 2009, 131, 12084-12085.

DOI: 10.1021/ja9052366

Capitalising on his analyses in Science (2007), Tim Jamison has developed a polyepoxide cascade reaction to build a polyether. He’s not the only one: Frank McDonald based a nice total synthesis last year on the same principles. However, Jamison has increased the numbers of epoxides, controlling formation of three ether rings.

First is construction of the linear, polyepoxy precursor - with a few surprises in Jamison’s route. The starting material is farnesol, providing three alkene groups, one of which is allylic, so was a perfect candidate for a Sharpless epoxidation. The isoprene-type unit was deactivated by oxidation of the terminal methyl group to an allylic alcohol and acetylation, allowing selective Shi epoxidaiton of the internal olefin. The acetate was then removed to restore the homoterminal alkene, and attention turned to the other end of the chain. An oxidation of the primary hydroxyl group and olefination provided the last site for epoxidation, which was again accomplished via an Sharpless epoxidation.

Right after, a molecular zipper was induced by NBS to form the polyether. Microsieves are essential, as Jamison notes in the Science paper, the presence of water decreases the stereo- and regioselectivity of the ring formations, whilst hexafluoroisopropanol is an interesting choice. He mentions that the highly polar and non-nucleophilic nature of HFIP ‘facilitate[s] the presumably cationic cascade and thus maximize[s] the directing influence of the methyl groups‘.

In this cascade reaction, the solvent choice provides such a nice result - all three desired ethereal rings form in excellent yield, with the remaining cyclic carbonate acting as a useful synthetic handle. Unfortunately, the bromination is unselective, with a pair of equally prevalent epimers. The group then finished the total synthesis with a very interesting sp2-sp3 Suzuki coupling followed by some deprotections.

A really nice work! Setting up those cascade reactions must be quite nerve-racking!