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Totally Synthetic by Paul H. Docherty, 11 June 2011

Total Synthesis of Aspidophylline A


L. Zu, B. W. Boal, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 8877-8879.

DOI: 10.1021/ja203227q

Garg’s total synthesis of Aspidophylline A is definitely a sweet synthesis. The target is a member of a large family of alkaloids isolated in 2007, bearing the somewhat unusual furoindoline moiety - none of which have been synthesized until now. There's a little biological significance, but Garg doesn’t waste any time discussing it!

The synthesis starts with interesting cycloaddition chemistry. Although ultimately resulting in a racemic synthesis, it's a neat way to set the relative stereochemistry, so it's not very surprising that this remains a popular strategy.

The next reaction - a Heck coupling - works well, the simplicity of the reaction is remarkable. No need for an electron rich partner - heating works.

It was then on to the title reaction, an ‘Interupted Fischer Indolization’, which proved a little more problematic. Their problem was a too flexible substrate, resulting in a slow [3,3] sigmatropic rearrangement of a hydrazine-type intermediate. They solved the lack of rigidity by tying the methyl-ester up into a lactone, and were proved correct in their hypothesis, returning a great yield of the indole intermediate. However, they didn’t even isolate it - the use of basic methanol resulted in reformation of the methyl ester, and aminal formation with the ethanolate group.

This rather neatly completed the final ring, leaving the group with only a deprotection and formylation to get to the target.