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26 August 2008 7,523 views 6 Comments

Panek and Lowe. Org. Lett, 2008, ASAP. DOI: 10.1021/ol801499s. Article PDF Supporting Information Group Website ResearchBlogging.org

More of a progress update than anything else, this paper, along with a previous report (DOI: 10.1021/ol0501875 Article PDF ) detail an interesting synthesis of Kendomycin.  I say progress update, as the synthesis plan was outlined in the latter paper, but it’s always nice to see a plan come together.

As is often the case, the bulk of the paper can be summarised in a (somewhat cluttered) retrosynthesis.  Much of the C9-C20 portion in built using relatively well known chemistry, so it’s to the other half that we should focus our attention.  The key to this is the completion of the highly-substituted DHP, for which (surprise!) Panek has developed an awesome methodology utilising a [4+2] annulation approach.

The two partners for the [4+2] are of some degree of complexity, and one has to look into the older paper to get the goods on the synthesis of the silane.  The key reaction is a Claisen rearrangement to take an enantiomerically pure allyic ester and rearrange into an allyl silane, generating a further stereocenter in the process.  (BTW, the SM is produced via hydrosilylation of a chiral propargyl alcohol, itself a product of enzymatic resolution).  I love this kind of chemistry…

The chemistry used to make the benzaldehyde partner was also of interest to me, as I hadn’t seen this particular reaction before.  The aldehyde comes from oxidation of the corresponding hydroxymethylbenzene.  This was made using a hydroxymethylation reaction – taking a phenol, and reacting with diethyl aluminium chloride and formaldehyde to install an ortho CH2OH.  Always good to learn something new…

So how’d that annulation work out (as if we didn’t guess…)?  Pretty good – cracking yield, transfer of stereochemistry and d.r., so I guess we couldn’t ask for much more.  However, the rest of the synthesis, whilst efficient and effective, didn’t quite grab me.  The abstract talks about the ‘underused samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction)’, which is certainly nice, but not remarkable.  Underused is probably correct, though.

What was interesting was the DHF synthesis in the closing stages.  The stage is set with an oxidation of an ortho-methoxy phenol with DMP, and then treatment with aqueous HF.  This promoted a demethylation of the remaining methoxy group, presumably via the Michael reaction suggested by Panek.

What happens next he leaves open to discussion, offering two potenial mechanisms that prompt DFH formation.  However, I’m having a slightly hard time understanding the differences in the mechanism (probably due to a nice, long bank-holiday weekend), but basically they look the same, just tautomerised.  In other words, probably a little bit from both column A and B…

Either way, this is a nice synthesis in support of some pretty cool methodology.

Lowe, J., Panek, J. (2005). . Organic Letters, 7(8), 1529-1532. DOI: 10.1021/ol0501875

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  • gilgerto says:

    I’ve always been amazed by the THF formation by annulation developed by Panek. In this reaction, an allylsilane adds to an alpha-hydroxy aldehyde (protected), producing a THF ring still containing the silane group which has moved one carbon apart it’s original position. It is kind of strange to me that desilylation did’nt occured to furnish simple addition product…

  • Madforit says:

    Sakuray allylation is great…usually that kind of reaction give E double carbon-carbon bond…annulation stabilize Z product..?
    an interesting method to make salycilaldehyde:phenol,CH2O excess,and SnCl4…you get metanol from formaldehyde reduction..

  • HPCC says:

    Madforit: during my Ph.D. I prepared the 3-phenyl-2-hydroxybenzaldehyde using MgCl2, Et3N and (CH2O)n. Such an easy reaction, works with every substrate, it seems. It was in a J. Med. Chem., just search that particular molecule in your favourite search engine. It didn’t seem to matter how dry MgCl2 was, so to me this easy-to-weigh solid has an obvious advantage over SnCl4. :)

  • Madforit says:

    a similar THP formation strategy was used in the one-step syntheses of hexahidrocannabinol twenty years ago…really great

  • WestCoast85 says:

    Good synthesis with a well know methology to do the furan moiety. A good alternative to the Amos B. Smith III approach with his Ferrier Petasis rearrangment to build the THF

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