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Totally Synthetic by Paul H. Docherty, 10 November 2009

Total Synthesis of Rubromycin


D. C. K. Rathwell, S.-H. Yang, K. Y. Tsang, M. A. Brimble, Angew. Chem. Int. Ed. 2009, 121, 8140-8144.

DOI: 10.1002/ange.200903316

The biological activity of Rubromycin is impressive, with inhibtion of HIV reverse transcriptase as well as human telomerase. We have only one stereocenter in rubromycin, and the synthesis is racemic. However, rubromycin is very difficult to make and has attracted many chemists (seventeen papers are referenced by Brimble) including work of Danishefsky and Kita, who succeeded in its total synthesis.

The synthetic problem is the formation of the ketal, which does not work with an acid mediated cyclisation. A thorough examination by Kozlowski and Reißig has shown that a late-stage cyclisation precursor with a fully elaborated isocoumarin domain is too electron withdrawing, so the analogous phenol doesn’t have sufficient nucleophilicity to form the ketal.

The solution, clear to Brimble, was to complete the ketal earlier, with a substrate featuring more favourable electronics. But they had to synthesise that precursor first. The formation of the naphthazarin moiety gets interesting very early. Brimble planned a Claisen rearrangement to install an allyl side chain, requiring an allyl enol ester as the precursor. She hoped this would work with a Michael type addition of allyl alcohol, and then elimination of a leaving group. However, when the leaving group (LG) was iodide, cine substitution was preferred over ipso. The solution was interesting: improving the electronegativity of the leaving group and thereby increasing the C-R bond polarity, whilst decreasing the effective size of the LG, and without loosing the leaving ability. This rules out fluoride, so they used azide as a pseudohalogen. A very interesting idea that tremendously increased the yield.

If allylation should be an easy transformation, how does methylation sound? Brimble doesn’t explain exactly why the group had to use such exotic conditions for a methylation, but fairly reducing conditions including a hydrogen atmosphere worked.

The naphthazarin half was finished shortly afterwards, allowing the group to move on to the isocoumarin-type system. Creation of the penta substituted phenyl ring was interesting, especially the bis-esterification using dimethylmalonate. Unification of the two fragments was done using an efficient Sonogashira coupling.

The group was then set for a ketalisation, using fairly mild acidic conditions, developed specifically for 5,6-ketals. This went fantastically, proving that adjustment of the reaction electronics was a winning strategy. Deprotection brought them to an intermediate in Kita’s synthesis, completing a formal synthesis. A very interesting total synthesis!