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10 November 2009 14,762 views 19 Comments


Brimble, Rathwell, Yang and Tsang ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200903316. Article PDF Supporting InformationGroup Website

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!


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  • Cascade says:

    How in the world can one install the stereocenter? Any ideas?

  • quinone says:

    it looks like the phenol autooxidizes when they try to methylate it, so they need the reducing conditions to prevent air oxidation

  • milkshake says:

    I second the quinone comment: the more el-rich a hydroquinone is, the faster it air-oxidizes under basic conditions. A colleague was making 1,2-dimethoxy-4,5-bis-(N-morpholino)-benzene. You get the intermediate, a deep-blue bismorpholino o-quinone easily by combining an excess of o-benzoquinone with morpholine. Piece of cake, but when he then reduced the quinone to colorless hydroquinone with Pd-C he had to work very fast – the hydroquinone was turning blue as soon as he opened the flask even before adding a base.

    • Fluorine says:

      I agree. have been working on naphtoquinones for quite a while now. the p-hydroquinone oxidises easily and deprotonation for alkylation even speeds it up.

  • antiaromatic says:

    I wonder if chiral phosphoric acids could lead to stereoinduction. Maybe the biaryl systems in something like VAPOL could get good enough stacking to form a nice tight ion pair that would favor attack from one side. Just a thought, though…

  • Gui says:

    Actually, fluoride would have been an excellent leaving group for that elimination. In E1cb reactions the nature of the leaving group is of little importance because the slow step is the attack of the nuclophile to the alkene.(Michael addition). Surely in the second step fluoride would be bad at leaving compared to azide but it really acelerates the first step (which is also the slow one) because of its strong inductive effect. Did they try fluoride or not :) ?

    • antiaromatic says:

      This is only true if altering the nature of the leaving group doesn’t substantially alter the rate of other steps of the reaction. If it does, it may be that the loss of fluoride becomes rate determining.

  • TWYI says:

    I think the issue wass getting the fluorine in there in the first place

  • Unfortunate says:

    Not to hijack things here, but I thought people in the community might want to know that Keith Fagnou from the University of Ottawa, who had earned quite a reputation in C-H activation and other areas of catalysis, passed away yesterday. Here’s the media release: http://www.media.uottawa.ca/mediaroom/news-details_1776.html

  • Jos Smos says:

    Wow, was just trying some of his chemistry for direct arylation that day…

  • umesh says:

    Thanks for the info. I thought only antisense drugs (oligonucleotides) are the class of telomerase inhibiors, its to good to see other class of compounds as contenders.