Total Synthesis and Stereochemical Reassignment of (±)-Indoxamycin B
There haven’t been many total syntheses recently that I’ve really wanted to write about in the last month or two, but I quite enjoyed both the Carreira offerings that appeared in Angewandte last Friday. After realising that I didn’t have time to write about both, I decided on this one as it reminded me of some chemistry I’d done myself a while back. I also enjoy it when total synthesis ends in reassignment, as it’s probably one of the more worthwhile outcomes of a synthetic campaign, and it makes a nice story.
Base image from http://mrsec.wisc.edu/Edetc/nanolab/photonic/index.html
Did anyone else see that paper on Thursday in Chem. Comm. titled "Use of Dimethyl Carbonate as a Solvent Greatly Enhances the Biaryl Coupling of Aryl Iodides and Organoboron Reagents without Adding Any Transition Metal Catalysts", and think "here we go again"? I immediately though it kind of appropriate that Chem. Soc. Rev. very recently published a history of transition metal contaminants in catalysis (DOI: 10.1039/C2CS15249E). However, on reading the Chem. Comm. paper, it seems the authors were very careful both to check all their reagents, and not make any grand claims. Not surprising, really, given the numerous examples of misunderstanding of such results in the literature. Even the title is cautious, saying 'without adding any transition metal catalysts', quite a step down from the bold claims of 'transition metal free' reactions seen in the literature of a decade or so ago.
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, 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.
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
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%. 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...
Here's an impressive total synthesis of schindilactone A by Tang, Chen, Yang, and 14 coworkers. At 29 steps in the longest linear sequence that's comfortably fewer than two per author. Still, the route is entirely linear and it's a fairly heroic effort, as we'll see.
Work began sometime ago as the group published syntheses of the ABC (Org. Lett., 2006, 8, 107) and FGH (Org. Lett., 2005, 7,885) fragments of the slightly more complex micrandilactone A some time ago. Apparently that unique, ketal spanned, 7-8 carbocyclic system in the middle took some time to work out. I'll cover the older work on those fragments as well, as it shows the origins of some of the key steps in the schindilactone A total synthesis.
Total Synthesis of Solanoeclepin A
Admittedly I don't check Nature Chemistry as often as I should, so I only noticed this truly epic synthesis of solanoeclepin A a few days ago. I remember being shocked by my first sight of the structure during a talk by Prof. Henk Hiemstra a couple of years back, especially that improbable looking DEF ring system. This synthesis is obviously a phenomenal technical achievement, and it must have been an incredibly demanding task, but at first glance there aren't too many sexy steps. The abstract mentions 'addressing one of the critical food issues of the twenty-first century' and solving natural supply problems, goals towards which this synthesis could be the first step.
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.
Note: I've never written a Tot. Syn. type post before, and it's come out a bit more detailed than I intended. I'll try and be a bit more brief next time...
Gram-Scale Total Synthesis of Iejimalide B
Here's a nice modern synthesis from the Fürstner group; an impressive panoply of transition metal mediated reactions were used in this highly convergent synthesis of iejimalide B (although perhaps a little more tin than some people would be comfortable with...). I think the best way to show this is with a retrosynthesis:
Not happy with just the first total synthesis of the iejimalides (Tot. Syn. here) back in 2007 and prompted by encouraging biological results obtained using the material from the first campaign the Fürstner group set about developing a 'truly scalable' route to these compounds, a goal I'd say they'd accomplished admirably. Apart the usual suspects (RCM, Stilles and a Heck) there's a few less common transformations which are worth a closer look.