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Totally Synthetic by Paul H. Docherty, 8 June 2009

Total Synthesis of Esermethole & Physostigmine


T. Bui, S. Syed, C. F. Barbas, III, J. Am. Chem. Soc. 2009, 131, 8758-8759.

DOI: 10.1021/ja903520c

Barbas calls this paper a ‘formal total synthesis of physostigimine’, as he actually stops at another natural product, esermethole. However, despite esermenthole is not mentioned in the title, the total synthesis of this compound is very interesting. Starting with a lightly functionalised indolinone, he is able to demonstrate a pretty wide variety of Michael additions to nitroolefins. These reactions were highly enantioselective and offered good diastereoselectivity in the case of non-terminal nitroolefins using Takamoto’s thiourea catalyst. Other thiourea based catalysts were also active, but offered only a reduced enantioselectivity of  less than 10% e.e..

So with the addition done, and a quaternary center in place, completion of the synthesis only took a few more steps. Reduction of the nitro group followed by carbamoylation allowed a reductive cyclisation to complete the cis-ring junction. This completes esermethole, with a reference to Overman’s work converging the syntheses. All that’s required is a deprotection followed by addition into an isocyanate to give the carbamate.

Interestingly, a similar piece of work by Nakamura turned up in Chemistry - A European Journal this week too:

Convolutamydine E is distinctly less complex, using a different approach to create a similar benzylic stereocenter. There’s even a similarity to the catalysts used in each synthesis. The limitations here are the scope of the paper, which is only communication, and that the addition chemistry is only demonstrated using acetaldehyde.

It’s be interesting to see how both of these reactions are adopted over the coming years!