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Totally Synthetic by Paul H. Docherty, 11 October 2009

Total Synthesis of Aigialomycin D


F. Calo, J. Richardson, A. G. M. Barrett, Org. Lett. 2009, 11, 4910-4913.

DOI: 10.1021/ol901979x

There is a twist in Tony Barret's total synthesis of aigialomycin D.With his interests in reactive intermediates, it comes of no real surprise that he builds the tetra-substituted phenyl ring late stage. A brief retroanalyis:

It turns out the that most parts of the molecule are commercially available. A chiral, homo allylic alcohol ((S)-(+)-4-penten-2-ol) was easy to buy, along with the diol, which generated from a sugar (three steps from 2,3-O-isopropylidene-D-erythronolactone). So with so much material easy to buy, really interesting is how, and what they used to make the phenyl ring:

Taking the dioxinone, and heating in toluene allowed a retro-Diels-Alder reaction to occur, that yielded a ketene as intermediate. The addition of the chiral homoallylic alcohol to the ketene gave them the required ester. Lastly, addition of of a base, followed by acid allowed cyclisation to give the required resorcinol ring, with the macrolactone precursor chains ready for a ring-closing metathesis. However, there was a small problem with this route, as the synthesis of the starting material was very low yielding. In the first route on the right, a lithium enolate adds to a Weinreb amide. The two steps totalled a 11% efficiency over two steps, so there was definitely room for improvement.

A second route involved a Claisen condensation approach; using an acid-chloride analogue of the Weinreb amide above, and a β-ketoester. The unnecessary allylic ester moiety was removed easily in the presence of a palladium catalyst.

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 combination of secondary / terminal olefin, the yield was inrcreased to 81%. Deprotection with a few protons did the business, and finished the target. A nice total synthesis!