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Totally Synthetic by Paul H. Docherty, 26 August 2008

Total Synthesis of Kendomycin


J. T. Lowe, J. S. Panek, Org. Lett. 2008, 10, 3813-3816.

DOI: 10.1021/ol801499s

This paper is a progress update, along with a previous report featuring an interesting total 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.

The paper can be summarised in a somewhat messy 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 dihydropyran (DHP), for which Panek has developed a very interesting methodology utilising a [4+2] annulation approach.

The two partners for the [4+2] annulation are complex molecules, and one has to look into the older paper to get the information 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 starting material 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.

So how would that annulation work out? Pretty good - excellent yield, transfer of stereochemistry and d.r., so I guess we couldn’t ask for much more. In a subsequent step, the abstract features a ‘underused samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction)’, which is certainly nice, but not remarkable.

What was interesting was the DHP synthesis in the closing steps. 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 a Michael reaction as suggested by Panek.

Panek offers two potenial mechanisms that prompt DHP formation. Basically they look the same, just tautomerised. Either way, this is a nice total synthesis in support of some pretty cool methodology.