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Aspidophylline A   

11 June 2011 10,743 views 7 Comments

Garg, Zu, Boal. JACS, 2011, ASAP. DOI: 10.1021/ja203227q Article PDF Supporting Information Group Website

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.

 

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7 Comments

  • See Arr Oh says:

    You can definitely see a little of Overman and Stoltz in Garg’s work. All three have this talent for mixing the old and the new in well-thought ways to make tight little alkaloids

  • gippgig says:

    The hydrazine-containing intermediate appears to be missing a double bond, which explains the inversion at the junction of the ester ring since steric hindrance causes the phenyl to attack that double bond from below. The positive charge might be on the other nitrogen atom.

  • J.J.L.C. says:

    This is a brilliant synthesis. Did you check out the footage from Garg’s after party celebration? This makes his synthesis look tame.

    http://www.youtube.com/watch?v=1CwYWlbaTKY&list=PL8FB8CFA7D8BB73E8

  • nicho says:

    My hats off to the Garg group, looks like they know how to play hard and extremely hard. This guy must have been a monster in the lab as a PhD, over 10 papers published! Now as a professor at UCLA he has 7 papers published and we are only half way through the year, way to bust your family jewels Garg!

  • SD chemist says:

    The first bracketed intermediate in the interrupted Fischer indole synthesis scheme above is missing a crucial double bond (which makes the [3,3] possible). Also, there should be 2 arrows to denote several mechanistic steps between that intermediate and the next one.

  • PaKul says:

    How many reactions can be “interupted” in such fascinating manner?!
    Bravo Garg!
    Thank you, Fischer!

  • Uuuuuups….what Harran is doing with his Cramm chair????? swicht the position to Garg