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Totally Synthetic by Paul H. Docherty, 7 August 2008

Total Synthesis of Nankakurine A & B


B. L. Nilsson, L. E. Overman, J. R. de Alaniz, J. M. Rohde, J. Am. Chem. Soc. 2008, 130, 11297-11299.

DOI: 10.1021/ja804624u

The alkaloids Nankakurine A and B induce ‘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. Unfortuanetely, a couple of postulated structure variations exist, so the group wasn’t entirely sure what the actual configuration of the spiro centre was. But let's start with the total synthesis:

One of the more subtle transformations I’ve described in a while, I was impressed by his use of enyne metathesis to construct a diene for a Diels Alder reaction.

The Diels Alder reaction was based on that utilised by Oppolzer in his total 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 an O-).

Cleavage of the weak N-N single bond with some samarium diioide, methylation via reductive amination of formaldehyde, and formation of the piperidine ring completed the target. A quick and very efficient total synthesis, that is based on Oppolzer's work.