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Totally Synthetic by Paul H. Docherty, 10 February 2009

Total Synthesis of Spirangien A


I. Paterson, A. D. Findlay, C. Noti, Chem. Asian J. 2009, 4, 594-611.

DOI: 10.1002/asia.200800445

After they finished Dolastatin, Ian Paterson's group put a focus on Spirangien A, that features an interesting pentaene moiety. However, Ian Paterson is interested in performing aldol reactions too.

Fortunately, the compound features a repeating stereotetrad fragment after dismembering the spiroketal, which can easily be contructed using aldol reactions if this was a full retrosynthesis. This key unit was build very quickly, starting with an enatiomerically pure ketone, and performing a 1,4-syn-aldol reaction using dicyclohexylboron chloride and methacrolein. This is a high yielding and stereoselective methodology, that Paterson has been using for decades. A diastereoselective reduction of the ketone then completed the unit, and they had two choices - Evans-Saksena (paper with Erick Carreira) or Evans-Tischenko (with Amir Hoveyda). The former was not only one step quicker, as the latter required saponification of the resulting ester, but also easier to scale up.

A few transformations allowed development of this fragement into the two components that were to be coupled. One required a further stereodefined hydroxyl group using a Myers’ alkylation, whilst the other used a cuperate addition to append the unsaturated sidechain. Forming the boron enolate of the ketone first, and then addition of the aldehyde allowed the coupling to complete, generating a reasonable yield and diastereomeric excess. Various attempts at improving this yield by altering the protecting groups on the partners were performed, but nothing was gained.

The mixture of products was then methylated at that troublesome C-23 postion, setting up the molecule for spirocyclisation, brought on by removal of the acetonide protecting groups. The result, as expected, is the doubly anomerically stabilised spiroketal. Happily, at this point the unwanted diastereomer could be removed, leaving the group ready to progress.

Treatment of this product with 9-BBN, to effect a selective hydroboration of the less-substituted olefin, provided a synthetic handle for elaboration. Oxidation and Stork-Wittig olefination gave them a vinyl-iodide, ready to build the pentaene system. As shown in the retrosynthesis, they were able to construct a symmetrical bis vinyl stannane, and simply had to choose which way to couple the smaller and larger fragments. Using ‘strict exclusion of light and employing base-washed amberised glassware‘, they tried both alternatives and found a favoured route. A very nice total synthesis!