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Totally Synthetic by Paul H. Docherty, 11 July 2010

Total Synthesis of Urechitol A


T. Sumiya, K. Ishigami, H. Watanabe, Angew. Chem. Int. Ed. 2010, 49, 5527-5528.

DOI: 10.1002/anie.201002505

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 its nature, leads to a racemic product with three new stereocenters. Again, the paper is a bit light on details - it would be nice to know why TiCl4 was the optimum Lewis acid, but there are a few references [1]. Their reasons are summarised by an avoidance of some unidentified side products - 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 a base was needed to prevent decomposition, presumably arising from protonation of the epoxide and rearrangement. Interestingly, that’s exactly what they did next - 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, a stereoselective oxidation and DHP formation installed the final ring. Hydrogenation completed this interesting total synthesis. Now, if only they could find some biological activity. Even milli-molar cytotoxicity…