B.R.S.M. Yield isn't everything


Top Five Syntheses of May/June 2011

Here's an idea for a feature I've not seen anywhere else that I thought I'd try. It wasn't easy to choose, and my tastes in chemistry may be different to yours. These are not in any kind of order, because that would be silly. Please point out any nice work I've missed in the comments!

KCN's first dithiodiketopiperazine

Total Synthesis of Epicoccin G [PDF][SI][GROUP]

DOI: 10.1021/ja2032635

K. C. Nicolaou et al.J. Am. Chem. Soc., 2011, 133, 8150–8153

I was contemplating doing a full write up of this when I started blogging at the start of this month, but I'm not sure I'll get round to it now, unless it's a quiet few weeks or people really want to see one (let me know!). KC chooses a fantastically non-obvious disconnection for this molecule; the two g-hydroxycyclohexanones are actually derived from two molecules of tyrosine using a neat oxidative dearomatisation procedure developed by Wipf, followed by dimerisation. These spend most of the route masked as the 1,3-cyclohexadienes only to be revealed in the penultimate step by a [4 + 2] with singlet oxygen, followed by a Kornblum - DeLaMare rearrangement. How often do you see those?

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Neodysiherbaine A

A Short and Efficient Synthesis of Neodysiherbaine A by Using Catalytic Oxidative Cyclization

T. J. Donohoe et al., Angew. Chem. Int. Ed., 2011, Early View; [PDF][SI][GROUP]

DOI: 10.1002/anie.201102525

Isolated a decade ago from a marine sponge, neodysiherbaine A is an excitatory amino acid and a powerful convulsant and glutamate receptor antagonist. There've been four syntheses to date; two by Sakai and coworkers in 26 and 23 steps respectively, one by Hatakeyama in 21 steps, and a considerably shorter one by Lygo and coworkers in 15 steps. Tim Donohoe and his group at Oxford saw room for improvement again, and published yesterday a sweet seven step synthesis showcasing their Osmium based methodology for the oxidative formation of cis-tetrahydrofuran rings.

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On Retrosynthesis, Logic and Swords

Dear internet, I'm a little busy this weekend, so please accept this rambling semi-rant and I promise I'll put up some real content soon.


Has anyone else noticed the variety of arrows used in retrosyntheses in the literature? A lot of people seem to be using closed arrows these days (for a recent example from someone who should know better, see the abstract of Baran's cortistatin full paper from last month), rather than the more traditional open ended ones (Þ).  I can't easily give an example of the incorrect kind above, because as far as I can tell there isn't a character for it in any font. That's because, as far as I know, it doesn't mean anything. The open arrow, on the other hand, predates the concept of retrosynthesis by a long way, as it's the logical operator for the  implication relation. So A Þ B means that the presence of A implies B. Which kind of makes sense. Eager to find a supportive quote from E. J. Corey, who coined the term retrosynthesis, I dug out my copy of The Logic of Chemical Synthesis, and was pleased to find the following:

"It is customary to use a double arrow (Þ) for the retrosynthetic direction in drawing transforms..."[1]

Excellent. However, during my search this sentence in the preceding paragraph caught my eye:

"Woodward’s account of the state of “organic” synthesis in a volume dedicated to Robert Robinson on the occasion of his 70th birthday indicates the spirit of the times. Long multistep syntheses of 20 or more steps could be undertaken with confidence despite the Damocles sword of synthesis - only one step need fail for the entire project to meet sudden death."

I've never heard anyone talk about the "Damocles sword of synthesis" before, but I think it nicely describes the feeling of impending doom which I've felt a few times during my time as a synthetic chemist. If you didn't get the benefit of a classical education, let me explain the origin of this phrase (with a little help from the wikipedia article).

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Named Reactions: The Hugershoff Reaction

Now over a hundred years old,[1] the venerable Hugershoff reaction is a great way to convert aryl thioureas to 2-aminobenzothiazoles.[2] Classically, an aryl thiourea in chloroform is treated with an equivalent of bromine at around room temperature then the product is just filtered off. The first step is believed to be bromination on sulfur, followed by electrophilic aromatic substition in the usual manner. Yields are generally good (in my experience), but it's important to get the electronics of the ring right - some activation is usually required, but if it's too electron rich then bromination on the aromatic ring can compete with bromination of the thiourea.

There's actually very little information on the reaction available through casual googling - it has no wikipedia page and I don't believe it's even been reviewed.[3] You're not limited to elemental bromine, with NBS and other halogenating reagents reported to work. A similar transformation (via a different mechanism) can be accomplished by treating aryl thioureas with iodine(III) reagents, or even DDQ.

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Solanoeclepin A

Total Synthesis of Solanoeclepin A

K. Tanino et al., Nature Chemistry, 2011, 3, 484–488; [PDF] [SI] [GROUP]

DOI: 10.1038/nchem.1044

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.[1] 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.[2]

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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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I’m sure glad I don’t use thiophosgene anymore

I doubt many people have used thiophosgene. Especially not as much as I have. For those that haven't experienced its penetrating odour and beautiful red colour, on balance I wouldn't recommend it. I used to use it for the second step in an (as yet unfinished) total synthesis of a natural product, to make an arylisothiocyanate, which meant using lots of it. I starting to bring more material through the route a few weeks ago and, performing the same step on 50 grams, was glad that I'd changed to using thiocarbonyl diimidazole (TCDI) the last time I had to do this. It's a pretty, bright yellow solid and far less malodorous; you can even weight it on a bench top balance (in the evenings and at weekends). It costs a bit more and isn't as reactive (my reaction takes 24 hours refluxing 1,2-DCE as opposed to a few hours at room temperature with thiophosgene), but on the upside it's not a war gas. TCDI is to thiophosgene what the ever popular carbonyl diimidazole (CDI) is to phosgene (also a war gas, but slightly better smelling).

So why bring this up? Well, today I needed to dry some carbon disulfide,[1] so I dug out the trusty lab copy of Amarego and Chai (or as most call it, and note the definite article here, 'The purifications book'). After finding the information I needed (distill it from CaH2 - who'd've guessed?) I glanced at the opposite page (always do this - you can learn a lot) and noticed that the entry for carbon tetrachloride listed the major impurity as CS2. That's a bit odd, right? I mean, they're quite different compounds. One's good for dry cleaning and global warming and the other's good mostly for eroding the inside of your face.[2]

Well, it turns out that back in the day a lot of carbon tetrachloride was produced from the reaction between CS2 and chlorine gas, via thiophosgene and trichloromethanesulfenyl chloride. In fact if you ever wanted to fall out badly with your coworkers you could even make your own thiophosgene from good old CS2 by stopping the reaction part way, and reducing down the CSCl4 intermediate with a bit of tin or sodium sulfide. You're having a bad day with Na2S is the least hazardous component in your reaction mixture. There's even an organic syntheses proceedure for the tin reduction, which somewhat redundantly points out 'the vapors formed in the experiment are very objectionable'. Don't do it. They don't pay you enough.

For a review on things you can do with thiophosgene,[3] see S. Sharma, Synthesis, 1978, 803 - 820.

[1] To quote from my supervisor's textbook on practical organic chemistry 'the use of this solvent should be avoided at all costs'. I share a lab with an inorganic group into nanotubes and fullerenes, and a postdoc of theirs used to run all his columns in carbon disulfide, claiming nothing else worked. They literally got though litres of it each day.

[2] According to the Merck index, pure carbon disulfide has a pleasant odour redolent of diethyl ether. A shame that you can't buy it pure enough to ever experience this. Even the stuff I distilled stinks. Apparently the culprits are OCS and thiols, which can be removed by washing with aq KMnO4 solution, followed by mercury. Or not.

[3] There are a few gems in here. For example, were you ever curious as to what happens when you mix thiophosgene with sodium azide and quench with dimethylamine? Me neither, but apparently 'the preparation is generally accompanied by violent detonations'.

Filed under: Lab, Serious | 34,020 views | 7 comments 6 Comments

Cyanolide A Aglycon

Total Synthesis of the Cyanolide A Aglycon

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

DOI: 10.1021/ja204228q

Update: the excellent See-Arr-Oh has guest blogged this at Tot. Syn.

Here's a hot target - this is the fifth synthesis of cyanolide A (fourth this year) since its fairly recent isolation in 2010 (see end of post for links). And it's not surprising given its potent activity against... snails. On a serious note, the reason for all the interest is the need for more effective molluscicides to eliminate the snails which act as hosts to the parasite responsible for schistosomiasis, which is common in the developing world, and sounds quite unpleasant. The double Sakuri reaction used here by Rychnovsky and coworkers here is a cool and original disconnection for this important molecule. Also, no protecting groups*!

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The Catalytic Enantioselective Total Synthesis of (+)-Liphagal

Stoltz et al., Angew. Chem. Int. Ed., 2011, Early View; [PDF] [SI] [GROUP HOMEPAGE]

DOI: 10.1002/anie.20110184

This tetracyclic meroterpene has had quite a bit of attention from the synthetic community since its isolation back in 2006 from a Caribbean sponge. Along with other well known natural products such as resveratrol, staurosporine, and wortmannin it's an inhibitor of phosphatidylinositol 3-kinase (PI3K), an enzyme involved in numerous diseases. The fact that those all have wikipedia pages is quite telling. It's also got some cytotoxicity towards various cancer cell lines, but I suspect the reason people keep making it is the unique and interesting 6-7-5-6 ring system.

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Iejimalide B

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

Fürstner et al., Chem. Eur. J., 2011, Early view; [PDF] [SI] [GROUP WEBSITE]

DOI: 10.1002/chem.201100178

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.

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