B.R.S.M. When all you have is a hammer everything looks like a nail


Welwitindolinones Redux

Perhaps not unexpectedly, given last year's exciting breakthrough syntheses, more synthetic work on the weltwitindolinones appeared in the literature last week, so I think an update is in order. As a reminder, the first synthesis of a bridged bicyclic member of this family came in March last year when Rawal reported a neat racemic route to N-methylwelwitindolinone D isonitrile, emerging as the winner of a 15 year race between plenty of well known synthetic chemists. This was rapidly followed by Garg, who published an excellent synthesis of (-)-N-methylwelwitindolinone C isothiocyanate in August, which I covered here.

Well, two more back to back JACS papers,[1] one each from Rawal and Garg have just appeared, and I'll summarise both here. Garg's describes improvements to the key step in his previously reported route to (-)-N-methylwelwitindolinone C isothiocyanate, along with the synthesis of (-)-N-methylwelwitindolinone C isonitrile and a couple of the so-called 'oxidised welwitindolinones'. Rawal's contains an asymmetric version of his previous racemic route, allowing access to (-)-N-methylwelwitindolinone C isothiocyanate/isonitrile, along with one of the 'oxidised welwitindolinones'. As Rawal’s has the most new chemistry of the two we'll look at that first.

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(-)-huperzine A

Update 02/09: just realised that Fukuyama's 2009 synthesis of (-)-huperzine was covered over at synthetic nature last year and the compound itself has a wikipedia page. Also, I notice that HMPA is mentioned in the paper. Whoops.


A Robust and Scalable Synthesis Of the Potent Neuroprotective Agent (-)-Huperzine A

S. Herzon et al., Chem. Sci., 2011, Advance Article; [PDF][SI][GROUP]

DOI: 10.1039/c1sc00455g

There's been a quite a lot of interest in this little natural product already, as it's known to be a potent and selective reversible inhibitor of acetylcholine esterase (AChE), with an impressive Ki of 23 nM. Apparently, recent studies have established that this property makes the compound a possible counter to organophosphate chemical weapons, such as the 'nerve gases' sarin and VX, which work by covalently modifying AChE (I, for one, am so glad I wasn't in that clinical trial). There's also some evidence it may be useful in slowing the progression of neurodegenerative diseases. However, the problem is (as usual) the difficulty of getting useful amounts of the darn thing for further studies - in this case the compound comes from a painfully slow growing chinese herb, with an isolation yield of just 0.011%. If my readership is what I anticipate then I expect you're all thinking, "that sounds like a job for total synthesis!", and you'd be right. The best asymmetric synthesis of (-)-huperzine reported prior to this work was that of Kozikowski and coworkers, published way back in 1991, standing at 16 steps with an overall yield of around 2.8%.[1] This new route by Herzon and coworkers manages a significant improvement on both counts, despite actually using the same chiral building block to introduce asymmetry...

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Kibdelone C

Porco et al., J. Am. Chem. Soc., 2011, Article ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ja203642n

Ready et al., J. Am. Chem. Soc., 2011, Article ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ja204040k

Here’s an odd occurrence; two quite different syntheses of the natural product kibdelone C in appeared in the JACS ASAP on the same day last week; one by the Porco group and another by Ready and coworkers. Each acknowledges the other for sharing details of the work before publication, so I guess the authors were less surprised than I was. There are a number of kibdelones, all of which are quite similar and tend to interconvert on standing. They boast antibacterial, antinematodal and anticancer activity. The mode of action isn’t known, but they look likely to bind nucleic acids.

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