Aigialomycin D

Barrett, Calo, Richardson. Org. Lett., 2009, ASAP. DOI: 10.1021/ol901979x. 

Macrolactones?  From Barrett?  It’s not his usual fayre, but as is more normal, there is a twist in the synthesis.  I think most chemists (or at least me…), when presented with a target like aigialomycin, would think about buying-in the aromatic portion, and then trying to bolt on the styrene-type olefin and building around.  However, with his interests in reactive intermediates, Tony Barrett (of IC, London… just down the road), it comes of no real surprise to me that he builds the tetra-substituted phenyl ring late stage.  Before delving into how he went about that, I though a brief retro would be in order.

It turns out the buying (much of) the rest of the molecule is quite an easy task.  A chiral, homo allylic alcohol ((S)-(+)-4-penten-2-ol) was easy to buy (though I’d bet pricey), along with the diol, which was bashed out of a sugar (three steps from 2,3-O-isopropylidene-D-erythronolactone).  So with so much material easy to buy, the really interesting bit is how, and what they used to make the phenyl ring.  It went a bit like this:

Taking the dioxinone, and heating in toluene allowed a retro-Diels-Alder to occur, leaving a rather open-looking ketene in it’s wake.  Addition of the chiral homo-allylic alcohol bit allowed addition to the ketene, giving them the required ester.  Lastly, addition of a bit of base, followed by a bit of acid allowed cyclisation to give the required resorcinol ring, with the macrolactone precursor chains ready to be RCMd together.  However, there was a small problem with this route, as the synthesis of the starting material was very low yielding.  The first route they used is on the right, and used a lithium enolate addition to a Weinreb amide.  The two steps to build this totalled a 11% efficiency over two steps, so there was definately room for improvement.

A second route involved a Claisen condensation approach; using an acid-chloride analogue of the Weinreb amide above, and a beta-ketoester.  The unnecessary ester moiety was removed easily, as it was allylic, and thus a touch of palladium removed it entirely.

At this point, all that remained was the RCM and a bit of deprotection.  Key to this was their use of a secondary olefin in addition to the terminal olefin; two terminal olefins resulted in a 50% yield.  However, using the secondary / terminal olefin combination, the yield was boosted to an altogether more satisfying81%.  Deprotection with a few protons did the business, and finished the target.  Nice!