Brimble, Rathwell, Yang and Tsang ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200903316.
Now for something rather different… indeed, we’ve only got one stereocenter in rubromycin, and the synthesis is racemic. However, one of the toughest and most commons lessons learnt when moving from total synthesis to medicinal chemistry is ‘just cause it’s flat, doesn’t mean the synthesis is easy’. Frankly, rubromycin is a bitch to make, and has attracted many a chemist to their folly (seventeen papers referenced by Brimble here…). However, tricky as it is, it’s not impossible – both Danishefsky and Kita have made it through.
So what’s the attraction? Well, the biological activity is impressive, with HIV-busting powers (reverse transcriptase), as well as activity against human telomerase. So what’s been the synthetic problem? Well, I presume most readers have examined the ketal, and thought about an acid-mediate cyclisation. Believe me, you’re not the first. But it doesn’t work. 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, meaning that 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 get that precursor first. The chemistry gets interesting pretty early, working on a synthesis of the naphthazarin moiety. Brimble planned a Claisen rearrangement to install an allyl side chain, requiring a allyl-enol ester as the precursor. She hoped this would simply be a case of Michael type addition of allyl alcohol, and then elimination of a leaving group. However, when the leaving group was iodide, cine substitution was preferred over ipso. The solution was neat – improve the electronegativity of the leaving group (thereby increasing the C-R bond polarity), whilst decreasing the effective size of the LG, and without loosing the leaving ability. Kinda rules out fluoride, so they used azide as a pseudo-halogen. Neat, and the result is a cracker.
If allylation should be an easy transformation, how does methylation sound? Piece-of-piss, right? Well, Brimble doesn’t explain exactly why the group had to use such exotic conditions, but a fairly reducing set of conditions was key, going as far as a hydrogen atmosphere. Anyone like to help me here?
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 quite neat, especially the bis-esterification using dimethylmalonate (a short aside – this substance is with no doubt my favourite lab chemical. I used buckets in my PhD, and cam so close to eating some of it. It smells so nice, but the ’98%’ in the title forced me to leave it alone…). Unification of the two fragments was done using an efficient Sonogashira, allowing the propargyl linker to be manhandled into a ketone by a bit of red-ox.
The group was then set for a ketalisation, using fairly mild acidic conditions (not the first set of reagents I’d have gone for though – my pot of pTSA would have been favourite…), developed by the group specifically for the purpose of making 5,6 ketals. This went fantastically, proving that adjustment of the reaction electronics was a winning strategy. A little deprotection brought them to an intermediate in Kita’s synthesis, completing a formal synthesis. Damn neat work, Kiwis!