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Totally Synthetic by Paul H. Docherty, 24 November 2006

Total Synthesis of Phorboxazole A


J. D. White, P. Kuntiyong, T. H. Lee, Org. Lett. 2006, 8, 6039-6042.

DOI: 10.1021/ol062530r

J. D. White, T. H. Lee, P. Kuntiyong, Org. Lett. 2006, 8, 6043-6046.

DOI: 10.1021/ol062531j

I was very surprised to see a total synthesis of a complex molecule like this in Org. Lett. today, but I’m afraid that after reading the papers, I’m less so. Obviously, the target has been around for years, and has been pretty popular, with syntheses by Forsyth, Smith, Williams, and Pattenden. Unsurprising given that high cytotoxicity! Anyway, the retrosynthesis:

As you can see, we’re not looking at anything particularly novel, but it’s certainly a well designed synthesis, with plenty convergency. The interesting reactions are the alkoxycarbonylations. This reaction was first investigated by Semmelhack in 1989, using stoichiometric palladium to effect the transformation. The White group used this as in the literature to create the A-ring as shown below.

However, White noted that the carbon monoxide was reducing the Palladium to Pd(0), explaining the need for a stoichiometric “catalyst”. Thus, adding an oxidant (excess p-benzoquinone), catalytic palladium dichloride bis(acetonitrile) was able to effect a similar transformation to create the B-ring in a similar fashion, though in only 58%.Without any directly comparable examples, it’s difficult to judge this methodology properly; palladium acetate is expensive, but loosing a significant proportion of the starting material is also expensive (they did recover 15-20%)…