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Totally Synthetic by Paul H. Docherty, 2 December 2009

Total Synthesis of 9-Isocyanopupukeanane


M. K. Brown, E. J. Corey, Org. Lett. 2010, 12, 172-175.

DOI: 10.1021/ol9025793

E. J. Corey, M. Behforouz, M. Ishiguro, J. Am. Chem. Soc. 1979, 101, 1608-1609.

DOI: 10.1021/ja00500a048


Corey's publication in Org. Lett. examines an interesting array of asymmetric catalysis - featuring a highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes. Such bridged dienes are also active ligands in a second asymmetric process: an enantioselective 1,4-addition of vinyl or aryl groups to unsaturated ketones. It’s this second reaction that is the centrepiece of this post, as it leads to an intermediate found in the 1979 total synthesis of the title compound.

Using a chiral-bridged diene produced earlier in the paper, that coordinates as ligand to a rhodium catalyst, allowed an asymmetric addition of the aryl (or vinyl) boronic acid. Interesting points are the vanishingly low catalyst and ligand loading, as well as the opportunity to produce the ligand in situ.

For the total synthesis, a transformation of the methyl ketone into the corresponding carboxylic acid is required. The haloform reaction is rather mild and requires only room temperature and six hours. The free acid was then chlorinated to the acid chloride, followed by Lewis acid mediated ring-closure onto the proximal aryl position. Alkylation with TOSMIC and methyl iodide provided -  after hydrolysis of the nitrile and methylation of the resulting acid -  an interesting intermediate. Demethylation of the methoxy group was a key step that promoted γ-lactone formation. Exhaustive hydrogenation of the arene using Nishimura’s catalyst generated three stereocenters with control presumably arising from the lactone bridge.

Right after the hydrogenation, the lactone was opened, reduced and tosylated, providing a nice leaving group. Treatment of the cyclohexanone with base then delivers the thermodynamically more stable enone preferred. Internal alkylation of this enolate gives the carbon skeleton of the target. The use of LDA would overwrite this preference resulting in cyclobutane formation.

A few more steps were required to install the isonitrile. This is a very interesting total synthesis!