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….