B.R.S.M. Help! I'm trapped in a molecule factory!

12Jun/1116

Cyanolide A Aglycon

Total Synthesis of the Cyanolide A Aglycon

Scott D. Rychnovsky et al., J. Am. Chem. Soc., 2011, Article ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ja204228q

Update: the excellent See-Arr-Oh has guest blogged this at Tot. Syn.

Here's a hot target - this is the fifth synthesis of cyanolide A (fourth this year) since its fairly recent isolation in 2010 (see end of post for links). And it's not surprising given its potent activity against... snails. On a serious note, the reason for all the interest is the need for more effective molluscicides to eliminate the snails which act as hosts to the parasite responsible for schistosomiasis, which is common in the developing world, and sounds quite unpleasant. The double Sakuri reaction used here by Rychnovsky and coworkers here is a cool and original disconnection for this important molecule. Also, no protecting groups*!

The route begins with the conversion of ethyl 3,3-diethoxy-2,2-dimethylpropanoate directly to the methyl ketone, which was then transformed into to the corresponding vinyl triflate in essentially perfect yield. This was then Kumada coupled to ClMgCH2SiMe3 to form the allyl silane later required for the key Sakurai reaction.

Cleavage of the diethyl acetal followed by an aldol reaction and hydrolysis gave the β-hydroxyacid in good yield. Don't forget that aldol reactions with acetate as the nucleophile are often a bit tricky and selectivity is often much worse than for higher homologs. The legendary Evans auxiliaries are pretty poor at this; the conditions eventually used above were developed by Sammakia (paper with lead references here). A few options exist for this kind of aldol, but other conditions with TiCl4 or SnCl2 unsurprisingly caused a lot of protodesilylation. I don't think the exact mechanism is known for this reaction; it probably goes via an open transition state, but as far as I know the cyclic case hasn't been ruled out yet. Anyhow, after hydrolysis the β-hydroxyacid was coupled with the secondary alcohol fragment shown under Yamaguchi conditions. Interestingly, this simple esterification is the lowest yield in the whole route, but the group resisted the temptation to protect up the free alcohol in the acid fragment. The synthesis of the alcohol fragment is worth checking out; there's some chemistry I've never seen before where the anion of (MeS)2CH2 (a formaldehyde umpolung reagent?) was used to open an epoxide then converted to the dimethyl acetal you see above. The endgame proceeded smoothly - the double Sakurai worked as planned and the exo-methylene groups were successfully unmasked to the β-alchohols. As conversion of this compound to Cyanolide A has been reported this completes the formal synthesis of the natural product. Sweet!

*your mileage may vary.

Previous syntheses:

Hong et al., Org. Lett., 2010, 12, 2880; Total, 10-ish steps (22%)

Reddy et al., J. Org. Chem., 2011, 76, 963; Formal (aglycon)

She et al., Org. Biomol. Chem., 2011, 9, 984; Total, cool alkoxycarbonylation

Yadav et al., J. Org. Chem., 2011, 76, 1922; Formal

Comments (16) Trackbacks (0)
  1. I think that should be LiCH2SiMe3 in the first reaction.
    An extra methylene slipped into the monomer for the Sakurai dimerization.

  2. Heh! Gippgig on top of things (he got me for the same over at TotSyn). Nice diagrams in this one, btw.

    • Your post over at Tot. Syn. is a really good read – I felt I’d wasted a good few hours when I saw it just after I’d finished writing this. This blog’s only been going a couple of weeks and I’ve not really been telling anyone about it until I get some more content up, so I guess I was bound to end up doubling up with the better established blogs at some point. A good synthesis like this is probably read and talked about by a lot of people. Hopefully I’ll find a niche in the community soon…

      • RE: niche – You could always do up a guest post over at TotSyn, and link back to your site.

        People are always looking (although they may not seem like it) for erudite but approachable discussions of the literature. Many just don’t have the time or access to look themselves, so they’re happy to have you guide them through it.

        The niche takes awhile (says the guy who doesn’t manage his own blog!). Just keep writing about good, current stuff, and people will find you.

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