B.R.S.M. The road to Tet. Lett. Is paved with good intentions


Oh, Sigma…

I'm a little busy with blog-syn and actual work at the moment, but a friend just sent me this screenshot from the Aldrich website, which I think I'll share with you all (annotation his):



Now, correct me if I'm wrong, but if I wanted to report a compound in, say, J. Med. Chem., I'm quite sure that TLC would not be an acceptable proof of purity. And if anyone knows how I can TLC quantitatively, please leave a comment, because I'm getting sick of running all these crude NMRs and HPLCs...

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Barium(ii) Iodide – The Shair Method

Full post on this synthesis to come when I get back from holiday at the weekend and can use ChemDraw! Sorry for the hand-drawn stuctures - I've still not found a good way to draw stuctures on my iPad, which is all I have with me.

I've never been particularly excited by phloroglucinol-derived natural products, but I really enjoyed Shair's recent synthesis of the polyprenylation acylphloroglucinol (+)-hyperforin (it's a PPAP!), which appeared in the JACS ASAPs a few days ago.


I'll hopefully get round to a more detailed discussion of the route in the next week, but the first step immediately caught my attention. The chemistry's simple enough - a good old-fashioned deprotonation step with t-BuLi, followed by treatment with  barium(ii) iodide and prenyl chloride. I remembered (after looking it up) that the prenylation is done via the organobarium to improve the regioselectivity of the reaction, a trick developed a couple of decades back by the Yamamoto group (J. Am. Chem. Soc., 1994, 116, 6130).

Still, I was curious about how the group carried out the reaction, and on what scale, so I delved into the SI (which, by the way, is excellent). There I found a slightly unusual tip for how to get the small barium pieces necessary to freshly prepare the BaI2:

"Using a hand drill hammer, a chisel, and a lead brick positioned on the laboratory floor, mineral oil-coated barium rod was portioned into approximately 25 mm segments... If a hand drill hammer and chisel are unavailable, a standard claw hammer and an appropriately-shaped shelving bracket may be employed in this step."

I'm not sure why, but seeing that in a JACS paper made me smile.



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Superlatives 3: The Longest Polyene

Update 02-12-12: If anyone wants/needs a copy of the original image without the text and arrow added, you can find it here.


Some of you may remember this synthesis of the world's longest polyene from a few months ago, covered by See Arr Oh here. I'm not going to say much about the the chemistry of this synthesis (Wittigs. Shedloads of 'em), or its significance, but I'd like to post a little addendum to the work here.

From Org. Lett., 2012, 14, 5496

I just got an email from a friend of mine who, upon reading the paper, asked the obvious question 'but what colour is it?'. Lycopene, of course, is famously red:

Image partly from wikipedia.org

Unable to find a answer to the question in the paper itself, or the Supporting Information he contacted the authors. After a few days, they sent a short reply and a beautiful image:

'the longest polyene is best represented by the vial on 7th from the left'

Now, how often do organic chemists get colours like that?

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Sunday Evening Maths 1: ovatoxin-a

Among other things in JACS last week (such as more exciting welwitindolinone stuff from Rawal and Garg), I noticed this enormous (and enormously toxic) palytoxin-type natural product (DOI: 10.1021/ja210784u). Although I'm not particularly excited as a synthetic chemist, and I don't understand the biology, I do like compounds like this because they're so silly.

Structural elucidation was a bit tricky as the group only got 700 μg of compound. They say that as a result they 'could not afford any reliable 13C spectrum', by which they presumably mean they couldn't afford the 6 months of NMR time it'd probably take to get a good one, or that the one they got resembled the black forest prior to the industrial revolution. That's 0.26 μmol for you.

Regarding stereochemistry, there are some 4,611,686,018,427,387,904 possible diastereomers for this behemoth, which sounds like a quite a lot. Thankfully, comparison with palytoxin allowed assignment of 28 of the 62 stereocentres, meaning that actually only 17,179,869,184 diastereomers are left. That's not bad, as they've straight away ruled out 99.999999996275% of the possible structures, without setting foot in the lab. Depending how precise you're being, that's all of them. The fairly hefty molecular weight of 2648.13 means that if someone made 1 mmol of each that'd be 45,441 tonnes of material. To put this is perspective, may I remind you that this is approximately the same weight of tomatoes exported by New Zealand every year (to 2 significant figures). The authors conclude:

"Eventually, the availability of pure OVTX-a, which is by far the main toxin produced by O. cf. ovata, heralds the potential of characterizing the risks it poses to humans as well as of establishing the tolerable daily intake for seafood consumers."

However, as  the 'mouse lethality assessment' found that:

"one to 3 min after injection, mice started wriggling and all died within 30 min with paralyzed limbs. These preliminary studies on OVTX-a’s toxicity led us to conclude that the toxin mouse lethality lies below 7.0 μg/kg."

I think I might play it safe and have none.


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Chemistry By Design

Update: I'm an idiot. Link fixed. That's what I get for copying and pasting from an email

I've just been made aware of this awesome project by Jón Njarðarson's group at the University of Arizona. You might already be aware of their excellent poster on the 200 best selling drugs (free to download and print!). Their newest gift to the synthetic community is a website which allows you to browse a number (>200) of inspiring syntheses and then test yourself on them. Aside from the obvious use of this, people without access to the literature at the moment, or people looking for good syntheses to prepare problem sessions on will probably find it a useful resource. The amount of effort that's gone into this is staggering (I certainly don't envy whoever entered all 54 steps of Steve Ley's epic azadirachin synthesis). I'll let Jón explain:

Dear Fellow Organic Chemists,


In a few weeks this project will also be available as a free APP for i-phones and i-pads.

With the help of my students we have added more than 200 total syntheses to the site, representing more than 100 different PI's and covering more than 40 years of publications. We plan to continue to add to the site, but we would like to encourage everyone to submit a synthesis they would like to see featured on our site. Instructions to do so can be found on the website.

Please share this link with everyone. I am convinced your students, post-docs, colleagues and many others will enjoy. This website should be a great supplement to graduate synthetic courses and advanced undergraduate courses.  Make sure to check out the QUIZ mode, which operates like a serial flashcard that allows you to test your synthetic knowledge (you can browse through each sequence in many different ways).

I hope you enjoy.

Best regards,


Tell the (synthetic) world!

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