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Nankakurines A and B   

7 August 2008 5,884 views 4 Comments

Overman, Nilsson, Read de Alaniz and Rohde. JACS, 2008, ASAP. DOI: 10.1021/ja804624u. Article PDF Supporting Information Group Website ResearchBlogging.org

As pointed out in the comments by some of the ‘yoof’ readership ‘The man [Overman] totally owns alkaloids'; indeed, this is definitely an Overman-type target.  The target(s) have been through a couple of postulated structure variations, so the group wasn’t entirely sure what the actual configuration of the spiro centre was.  However, the smart money was on the configuration shown (and borne out in this synthesis).

Biological profiling of this small family has been distinctly limited.  However, the signs point to induced ‘secretion of neurotrophic factors and promoteneuronal differentiation of rat adrenal PC-12 cells’.  Overman explains that such neurotrophic species have roles in neurodegenerative disorders such as Alzheimer’s
and Parkinson’s, so are of considerable interest.  But lets stick with the synthetic action:

One of the more subtle transformations I’ve described in a while, I was impressed by his use of ene-yne metathesis to construct a diene for a Diels Alder.  It’s one of those reactions that is deceptively simple, but consider alternatives for the construction of the diene – not so favourable, are they?!

The Diels Alder in question was very-much based on that utilised by Oppolzer in his synthesis of the related lucidulin; control of stereochemistry was excellent.  A few more steps and they were ready for the impressive intramolecular azomethine-imine cycloaddition.  This step is also remarkably similar to one used in Oppolzer’s work; the latter work used an intramolecular alkenylnitrone cycloaddition (substitute the BzN- for a O-)

Cleavage of the weak N-N single bond with some samarium diioide and methylation via reductive amination of formaldehyde left them with only the piperidine ring to form to complete the target.  A quick and very efficient synthesis, but it does lean on the Oppolzer work rather heavily…

Nilsson, B.L., Overman, L.E., Read de Alaniz, J., Rohde, J.M. (2008). Enantioselective Total Syntheses of Nankakurines A and B: Confirmation of Structure and Establishment of Absolute Configuration. Journal of the American Chemical Society DOI: 10.1021/ja804624u

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