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Totally Synthetic by Paul H. Docherty, 27 June 2007

Total Synthesis of Spirotryprostatin B


B. M. Trost, D. T. Stiles, Org. Lett. 2007, 9, 2763-2766.

DOI: 10.1021/ol070971k

Eight steps to the natural product; we’ll start with step one (or rather, the first non-literature step):

We’ve looked at Otera’s catalyst before, but as a quick reminder, it’s a transesterification catalyst. It’s been known for a little while, and the mechanism is in this JOC article. Nice to see it being used.

Deprotonation of this malonate-like β-dicarbonyl allowed displacement of vinyl tosylate to append an oxindole, creating the starting material for the synthesis-defining prenylation. The concept for this reaction is that upon treatment with palladium, addition of metal to the allylic ester will allow decarboxylation and generation of a good carbon-centered nucleophile. This then readds to the allyl-palladium species to generate a new quaternary stereocenter.

As Trost points out, this is similar to the palladium-mediated Carrol rearrangement, examined by both Tsuji and Saegusa. However. a difficulty in this case is the regioselectivity of the prenyl addition, as the anion generated by decarboxylation is an extended enolate of a fashion, and could react in many positions. However, a bit of hard work resolved this in good fashion, optimising to a cracking yield and dr.

Completion of the synthesis took a few more operations, using Sharpless chemistry to add phenylselenium acetate across the prenyl group, and then eliminate again by in situ oxidation. Finally, the last ring was to be put in, but the usual suspects, palladium and copper were somewhat reluctant. However, success was had with trimethyl aluminium, attributed to its ability as both a “Brønsted base and a Lewis acid”. Nice!