Garg, Zu, Boal. JACS, 2011, ASAP. DOI: 10.1021/ja203227q
So – when one ‘old-schools-up’ a synthesis, is that a homage, or just ho-hum? I guess it comes down to two things – the reactions used, and the overall synthetic strategy. Use them in the correct manner, and it comes across as the sweetest synthesis; or alternatively as a [ctrl-C] [ctrl-V] bore-fest; Garg’s synthesis of Aspidophylline A is most definitely the former.
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 synthesis until now. There’s a little biological significance, but Garg doesn’t waste any time discussing it, so neither shall I!
The synthesis kicks-off with a tasty piece of cycloaddition chemistry – and I guess this is what makes me think of synthesis from the days of teak benches, smoking in the lab and nobel-prizes for total synthesis. 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 old-school reaction isn’t really all that old, but the Heck coupling’s position in the history of catalysis still qualifies it as far as I’m concerned. And when it works well (as in this case), the simplicity of the reaction is remarkable. No need for an electron rich partner – just tickle it with the bunsen (or suitably safe alternative) and let it rip. And that ring conformation means that the bicycle formation is a stereochemical certainty.
It was then on to the title reaction, an ‘Interupted Fischer Indolization’, which proved a little more problematic. Their undoing 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 – chucking in a little 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.