Physostigmine & Convolutamydine E

Barbas, Bui, Syed. JACS, 2009, ASAP. DOI: 10.1021/ja903520c. 

Now, this is a bit of a fib already. I’m not entirely sure of Barbas’ reason for calling this paper a ‘formal total-synthesis of physostigimine’, as, whilst it is a formal synthesis, he actually stops at another natural product, esermethole.  Now, this is fine – and it’s still a formal synthesis of physostigimine, but it is moreso a total synthesis of esermethole.  Why he felt the need to call this a formal synthesis I don’t know.

It’s a shame to dwell on this, though, as the synthesis is pretty sweet.  Starting with a lightly-functionalised indolinone, he is able to demonstrate a pretty wide variety of Michael additions to nitro-olefins.  Not only were these reactions highly enantioselective, he was also able to demonstrate good diastereoselectivity in the case of non-terminal nitro-olefins.  This was done in conjuction with a fair-old catalyst screen, turning up Takamoto’s thiourea catalyst as the winner.  Other thiourea-based catalysts were also active, but the difference between >90% e.e. and <10% e.e. was remarkable WRT catalyst design.

So with the addition done, and a quaternary center in place, completion of the synthesis only took a few more steps. Reduction and ‘protection’ of the nitro group allowed a reductive cyclisation to to complete the cis-ring junction, with somewhat unsurprising diastereoselectivity (making the trans- fused analogues is tough).  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 – so no real sweat (though it’s worth examing Overman’s yield-issues in the original paper…).

Interestingly, this a similar piece of work turned up in Chemistry – A European Journal this week too…

Nakamura, Hara, Shibata, Takeshi. Chem. Eur. J, 2009, EarlyView. DOI: 10.1002/chem.200900944.  

So the compound we’re making here is distinctly less complex, using a different approach to create a similar benzylic stereocenter (an aldol in this case).  There’s even a similarity to the catalysts used in each synthesis.  The limitation here is the scope of the paper (which is only a Chem. Eur. J. communication) – the addition chemistry is only demonstrated using acetaldehyde, something the authors seem quite happy about.

It’s be interesting to see how both of these reactions are adopted over the coming years.  Nice work all around.