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Totally Synthetic by Paul H. Docherty, 10 January 2010

Total Synthesis of Isatisine A


A. Karadeolian, M. A. Kerr, Angew. Chem. Int. Ed. 2010, 49, 1133-1135.

DOI: 10.1002/anie.200906632

This short synthesis by Michael Kerr of the University of Western Ontario is very interesting. The rationale for its investigation is also pertinant, as it turns out that Isatisine A is a moderately active HIV isolate (EC50 of 38 ÁM). Unfortunately, the compound that reluctantly streaked out of the final column was the syn-acetonide. This was initially thought to be the target, but resulted from eluting the column in acetone…

The synthesis starts with a very neat reaction; a Johnson tetrahydrofuran synthesis, using a cyclopropane, an aldehyde and a Lewis acid. This reminds me of a lot of recent work with gold; the similarity clearly comes from the fact that most gold complexes are Lewis acids. Full details on the reaction are found in a recent publication in JACS. The mechanism involves an "intimate ion pair pathway".

Kerr seems to be disappointed in the diastereoselectivity of this reaction as the result was a 11:1 cis:trans mixture. I’d be happy enough, but no matter, as it’s improved later in the synthesis. With two chiral centres fixed, it was time to functionalise the THF. The suspicious looking differentiated malonate was up for its starring role next, as the benzyl ether was predictably 'saponified' by hydrogenation, and fitted up with an allyl ester. This could then be decarboxlyated using palladium, resulting in a 2,5-dihydrofuran. As you can all guess at this point, dihydroxylation with substrate controlled conditions (methanesulfonamide, NMO, OsO4) provided a pair of stereocentres, protected up. The tosyl group was then removed from the indole using magnesium metal in methanol.

This left them set for the appendage of an indole, allowing with a bit of oxidation. In two steps, they form an epoxide on the existing indole, which was attacked by the free alcohol (which looks somewhat remote, but this is a cisoid THF). The resulting aminal is perfectly set to be C3-indole alkylated, requiring only an acid to facilitate this. In practice, the reaction was initially favouring the incorrect epimer, but isomerisation in acid allowed an equilibration to occur, giving a 3:1 ratio in favour of the desired isomer after 24 h. A more satisifying 6.3:1 ratio can be isolated after 42 h, with concommitant lactamisation, and delivery of the protected natural product. A very interesting synthesis.