Urechitol A
Watanabe, Sumiya, Ishigami. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.201002505. 
[No SI available]
As much as biological activity is a great rationale for working on a molecule, I do like it when a group does the chemistry for the chemistry. To quote Watanabe, ‘Although urechitol A itself exhibited no biological activity, its unique tetracyclic structure prompted us to investigate its synthesis‘. And when a group can make such an interesting molecule without too much resource, why not? Key, of course, was building that fascinating cycloheptane, featuring not one, but two oxa-bridges. Their plan was to build this using a [4+3] cycloaddition between a furan and a silyloxyallyl cation – a reaction that could create one of either of the oxa-bridges. Through a little experimentation (which is unfortunately not published), the route shown was favoured, as it was far cleaner.
The reaction, by it’s nature, lead to a racemic product, but three new stereocenters can’t really be sniffed at, especially as the product is so obviously suited for the target. Again, the paper is a bit light on details – it’d be nice to know why tickle-four was the optimum Lewis acid, but there are a few reference [1 - a nice Organic Syntheses prep, 2, 3]. Their reasons are summarised by an avoidance of some unidentified crap – perhaps not the most scientific of explanations…
Moving on from here, the molecule is nicely functionalised, allowing the group a lot of freedom for their next move. They decided to install the other oxygen bridge, and to do this via an epoxidation. Using the simplest methods such as mCPBA were ‘less effective‘ – and a bit of base was needed to prevent decomposition, presumably arising from protonation of the epoxide and rearrangement. Interestingly, that’s exactly what they did next – a bit of pTSA in methanol promoted opening of the epoxide and a decent yield of the tricyclic structure.
A few oxidations, and a couple Grignard additions (all stereoselective in their favour) later, and the group were ready to do the final work on the target. Using the Lemieux–Johnson conditions (yes, that’s the name for this!), a stereoselective oxidation and DHP formation installed the final ring. A little hydrodge tied things off, and completed a rather neat synthesis. Now, if only they could find some biological activity. Even milli-molar cytotoxicity….
(2 votes, average: 4.50 out of 5)
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There’s an extra methyl in the first & last structures (top left).
I hope the lack of a SI isn’t a new feature of ACIEE. Interesting synthesis nonetheless.
Nice write up, Paul! Pretty nice 4+3…. and I think its a hemiacetal, not a mixed acetal.
No SI is total bullcrap. Haven’t they learned from the LaClair mess?
I wonder if some of their low yield in the 4+3 was from the competing 2+3. It seems to me that it would be feasible to have the furan add to the hemiacetal followed by nucleophilic attack of the silyl enol into the resulting oxocarbenium ion.
I imagine they would have tried SnCl4 for the 4+3…
synthesis are getting boring…we need somthing Baran
I this really good enough for Angewandte ?
ok, ok only kidding……………..
This is little bit unrelated to the topic.
Three different synthetic efforts (methodology) has been published in nature and science in June.
1. Scott Miller’s peptide catalysis in Science (June 4)
2. Buchwald’s palladium catalysis (trifluoromethylation of aryl chloride) in Science (June 25)
3. Johnston’s amide synthesis in Nature (June 22/23)
Good work overall by synthesis community.
Never heard of ” Lemieux–Johnson conditions “?
Oh, I’ve used these conditions many times, but people very rarely attribute a name to them!
Was the ‘Lemieux-Johnson’ step run in MeOH – otherwise where did the methyl group come from? Also, does that mean that the hemi-acetal formation requires the oxocarbenium ion to close rather than just the aldehyde? or does the methoxy product represet a thermodynamic sink?
No MeOH needed although I thought the same thing at first. Paul’s structure should have an OH instead of an OMe there. The 3D structure has it depicted correctly though.
Royal Society predicts ‘game over’ for British science.
Nature: 10.1038/466420b
I don’t understand why UK puts a lower value in basic science research…