Trost, and Stiles. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070971k.
He’s done it . Those of us who read Tenderbutton from the start will have known of Dylan’s work on this tasty little number, and he’s done it proud. 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 funky trans-esterification catalyst. It’s been known for a little while, and the mechanism is in this JOC article. Nice to see it being used; what was it like to handle, Stiles?
Deprotonation of this malonate-like Î²-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 re-adds 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 by Dylan 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 it’s ability as both a “BrÃ¸nsted base and a Lewis acid”. Pokey, but nice.
Good job, old chap!