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Totally Synthetic by Paul H. Docherty, 17 August 2006

Total Synthesis of Amurensinine


U. K. Tambar, D. C. Ebner, B. M. Stoltz, J. Am. Chem. Soc. 2006, 128, 11752-11753.

DOI: 10.1021/ja0651815

Another short but sweet synthesis by Stoltz, this time of the isopavine alkaloid amurensinine (or at least the enantiomer of the natural product). The biological activity of this target is certainly appealing enough, as it seems to be interesting with regard to Parkinson's and Alzheimer's disease. Their synthesis involves C-C and C-H bond insertions, the former with an aryne. Let's start with a bit of C-H activation:

Maybe you have met such chemistry in your undergrad course, but it’s nice to see a real world example with a very high yield! But there’s a thorny selectivity issue - why only one regioisomer, and why that one? No answer in the paper, even though the same question is posed. Perhaps it’s because the hydrogen is para to a methoxy group, or is it just steric effects… but I can’t actually believe that. On with the C-C activation:

Now that’s an interesting transformation. Taking the product of the former reaction, and treating it with an aryne, they get addition and then rearrangement to get to the product in a good yield. With this substrate in hand, they did a diastereoselective reduction with L-Selectride, and an oxidative resolution to set up the asymmetry, requiring only a few more steps to get to the target.

Selected Comments

18 August, 2006 at 15:42, aa says:
The selectivity issue here can also be attributed to an electronic contribution (although I would say that sterics is the dominating determinant), if this does follow a Friedel-Crafts related mechanism. Relatively speaking, the para position of anisole is more electron-rich than the ortho because of the inductive electron-withdrawing effect of oxygen counteracting the electron-donation by resonance. Some evidence against a purely steric argument:

In my own work on Friedel-Crafts acylations I have observed >99:1 selectivity for intramolecular acylations using 3,4-dimethoxyphenyl substrates. As well, the 3,4-methylenedioxyphenyl substrates, where the steric bulk of the substituents has been decreased substantially, gives the same selectivity. Food for thought…