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Platensimycin   

24 July 2007 4,842 views 15 Comments

platensimycin.jpg

Yamamoto, Li and Payette. JACS, 2007, ASAP. DOI: 10.1021/ja073590a.

I know what you are thinking; not that f*cking molecule again! However, this approach by Yamamoto is really quite elegant, and contains some amazing transformations. I’m not going over the biology again – it’s all here: it would also be appropriate to point out this is a formal synthesis, heading for an intermediate found in other syntheses containing the challenging tetracyclic core. I’ve also not bothered with a retrosynthetic analysis (such a slacker, I know…), but their work differs from previous approaches by not forming the ether by alcohol addition to an alkene, but via a Robinson annulation.

On with the synthesis… Their work kicks-off with an asymmetric Diels-Alder on methyl cyclopentadiene and methyl acrylate using their BLA (Brønsted acid assisted chiral Lewis acid) catalyst; awesome result! This approach seems very “Corey” to me, and reminds me distinctly of his work on similar systems in his total synthesis of prostaglandin F2a (:)). They then deprotonated the ester, and did a nitrosoaldol to give the N-nitroso species. This was then decarboxylated to leave the desired ketone. Nice!
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The next few steps to the Robinson precursor are nicely planned, and are executed with rather decent results, other than an unfortunately unselective cyanide addition to a lactol. I’m surprised at the lack of selectivity here, and also the choice of reagent: diethyl aluminium cyanide can’t have been at the front of the fridge! However, they explain that this was a LA-mediated addition, which makes some sense to me, but I think I’m not quite getting it…

A few more steps and they were ready to cyclise, using stoichiometric L-proline to control the addition to the Si face of the enone. This reinforced the substrate induce bias to achieve a 5:1 d.r., better than the 3:1 achieved using the unmatched D-proline case. The sodium hydroxide that follows then dehydrated (aldol style) to give the desired intermediate.
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This paper was a good read, and an excellent synthetic plan. However, I wish it had been one of those fancy new three-page JACS communications…

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15 Comments