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Totally Synthetic by Paul H. Docherty, 17 December 2006

Total Synthesis of Phorboxazole B


B. S. Lucas, V. Gopalsamuthiram, S. D. Burke, Angew. Chem. Int. Ed. 2007, 46, 769-772.

DOI: 10.1002/anie.200603656

We covered the reasons for making Phorboxazoles fairly recently in James White’s total synthesis of the Phorboxazole A last month. I also pointed out that these natural products have been very popular, with a further two syntheses of this complex molecule, by Evans and Zhou. At first glance of this paper, I wasn’t particularly impressed, as much of the work has been seen in other syntheses, and seemed pretty standard chemistry. However, looking beyond the retroanalysis and into the fragment synthesis, a fine body of methodology development can be seen. Anyway, on with that relatively mundane retrosynthesis:

To me, whilst those disconnections are perfectly valid, there’s not a lot to learn here. So on with the synthesis, starting with the C33-C39 lactone. The made this in a very impressive chelation-controlled hetero-Diels-Alder reaction of the mannitol-derived aldehyde with Brassard diene, using a Europium complex. This work was originally developed by Danishefsky, in this JACS paper.

The synthesis of much of the rest of the molecule is covered in a pair of Org. Lett. publications (1, 2) and a JOC article. Their approach to the complex complex bis-tetrahydropyran unit was to use a two-directional synthesis followed by palladium-mediated desymmetrisation. The symmetrical tetraol substrate for this was achieved very quickly, using an ozonolysis of cyclohept-5-ene-syn-1,3-diol, and indium mediated allylation followed by metathesis, completing the cyclisation substrate.

The ground-work for this type of cyclisation was developed by the palladium specialist Trost, along with F. Dean Toste in their seminal paper in JACS. Their model suggests that usage of a [(R,R)-DPPBA] reagent-controlled double cyclisation would desymmeterise the substrate, producing the desired chiral product. Their paper discussed the "chiral pocket" of the catalyst as being critical in the transition state:

Optimisation of the conditions then allowed the group to deliver a 75% yield of the product in 98% e.e., along with 12% of the meso product (further rational of this step is given in the second paper in Org. Lett.; I’m not transcribing the whole paper, but it is a must-read!).

Although the two ends of the molecule are now different, it still takes careful elaboration to functionalise one end without disturbing the other. However, the group managed this using a Sharpless dihydroxylation, using the conformation of the six-member rings to control this. Only the less hindered, equatorial vinyl group reacts in their hands, stopping the incomplete reaction after three hours and recycling the unreacted starting material.

So, in other words, an impressive synthesis, leaving you folks with plenty to read!