B.R.S.M. To strive, to seek, to find and not to give a yield


You may have noticed some… changes…

Hi all! Although this news is actually over a week old (and things are still in progress), I have an announcement to make. As many of you may have noticed, my old webhosting sucked - my domain was unmemorable, and when you did find the site it was often down for some reason. Well, thanks to a generous gift from DrFreddy over at Synthetic Remarks I now have a new domain name, and some decent hosting to back it up! So, the reason for this post is twofold: firstly, to tell you all to update your bookmarks for I can now be found at brsmblog.com and secondly, to again thank DrFreddy for helping out a poor student - this is easily the nicest thing anyone's done for me all year!

By way of warning I should say that the database which powers the blog is still over at eristocracy.co.uk, which is slowing things down at the moment but it will hopefully be migrated soon, as are the schemes of posts written before last week because I can't seem to get the links to change to the new server. When these issues are resolved then everything should be much better. In the meantime, please be patient and expect things to be a little shakey for the next week or so while I work things out!


Filed under: Not Chemistry, Serious | 14,294 views | 1 comment 1 Comment

Resources List

One thing I've been meaning to do for a while is put together a links page for online resources (other than journals or blogs) that might be of interest to postgraduate chemists. I've noticed a few times recently that I'll talk to someone about a particular reaction and then tell them there's a great explanation in Andy Myers' Chem 216 notes, Baran's heterocyclic chemistry handouts or Dave Evans' lectures and they'll just stare at me blankly. Likewise, a number of groups make their group meeting presentations freely available and I've learnt a lot from reading some of these. So, below are sites I've found to be useful, but I'm sure/hoping there are lots of good ones missing so don't be shy and point them out in the comments!

Filed under: Ask the audience, Serious | 25,182 views | 19 comments Continue reading

Black dot… I mean Linstead notation.

Anyone who's read some of the older chemical literature (or even recent papers by old school chemists) has probably noticed the 'black dot' notation used to depict stereochemistry at ring junctions, particularly by chemists in the US and Canada. Here's a recent example, so you'll know what I'm on about if you don't already.


From Angew. Chem. Int. Ed., 2010, 49, 4864 – 487.[1]

I don't know how things are in the US, but at no point during my chemical education do I ever remember having this notation explained to me. I recall encountering it for the first time at the start of my PhD, asking around a bit, and then just working it out for myself. Turns out it's actually really simple - a black dot at a ring junction just means that the hydrogen there is on the β-face, i.e. above the plane of the paper. To this day I've never seen this explained in a textbook, and have wondered from time to time where the heck it came from. As named reactions become canonised, the references the seminal papers slowly disappear, and clearly the same thing has happened here, as with many other conventions and nomenclatures. However, not having a name for this notation I'd never been able to trace where it started. Until now.

Filed under: Literature, Named reactions, Serious | 18,037 views | 10 comments Continue reading

Solve your deprotection problems… with TNT

A busy week in the lab trying to finish this damn natural product. More things at the weekend.

Update 30/07/11: Forgot to give a reference for the Hoffmann paper, which is Angew. Chem. Int. Ed., 1993, 32, 101-103. It's not a bad piece of work, and was for a time the shortest route, despite being entirely linear.

Johann Mulzer, one of my favourite chemists, wrote a review back in 1991 titled 'Erythromycin Synthesis—A Never-ending Story?'. It's well worth a read as these natural products have inspired an awesome body of work, and were an important benchmark in stereoselective natural product synthesis for many decades. Woodward, Stork, Corey, Danishefsky, Evans, Paterson, Reinhard Hoffmann, Mulzer, Carreira and most recently White have all worked on them, which is some recommendation.[1]

Anyway, I was reading Hoffmann's synthesis of (9S)-dihydroerythronolide A today when I encountered a most unusual set of conditions for deprotection. To set the problem in context, the (unstable) triply protected compound below had been obtained, and only three steps remained to the glorious completion of the target; selective cleavage of the cyclopentylidene acetal, macrolactonisation (assisted by the conformation limiting p-methoxybenzylidene acetals) and a final deprotection. The problem was that the cyclopentylidene acetal couldn't be removed without cleaving the other protecting groups, despite encouraging results obtained earlier in model studies. Not wanting to start again, a method to slow down hydrolysis of the p-methoxybenzylidene acetals was needed.

Filed under: Fun, Lab, Serious | 18,556 views | 4 comments Continue reading


A second post this weekend - you guys are lucky the weather is awful here!

Total Synthesis of (+)-Omphadiol

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

DOI: 10.1002/anie.201102289

Omphadiol is an africanane sesquiterpene isolated for the first time in 2000 from a basidiomycete. No-one knows what it does because of the small amounts isolated, but structurally similar sesqui- and diterpenes exhibit various biological activities including antiviral, anti-inflammatory and anti proliferative effects. It’s also got an interesting 5-7-3 ring system and 6 contiguous stereocentres around the ever popular trans-hydroazulene core. That notwithstanding, it took Daniel Romo and coworkers at Texas A&M University just 10 steps (and not a single protecting group) to prepare the natural product stereoselectively from (R)-carvone via a bicyclic b-lactone intermediate. 

Filed under: Current Literature, Serious, Total Synthesis | 26,093 views | 4 comments Continue reading

BIBS, the newest silicon protecting group

Note: I'm currently on holiday. I do have internet access, but drawing chemical structures on the netbook I've borrowed may just be too painful. I'll try and get some updates out ASAP.

Di-t-butylisobutylsilyl, Another Useful Protecting Group

Corey et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]



I suspect that anybody who’s been engaged in synthetic chemistry for more than a year or two has probably used a silicon protecting group. I’ve used plenty, and they’re generally very useful, easy to put on and take off, and pretty robust under a lot of different conditions. One of the great things about these groups is the huge range available; from the labile TMS and TES, to the more robust (and useful) TBS and TBDPS, to the hardy TIPS.[1] At the extreme end of the scale an even tougher group is the tri-t-butylsilyl group, but that’s very hard to put on or take off, and the silylating reagent itself is a pain to make. This week Corey published an attempt to fill the niche for a group tougher than TIPS, but more useful than tri-t-butylsilyl, with the disclosure of the di-t-butylisobutylsilyl (BIBS) group.

Filed under: Current Literature, Serious | 32,286 views | 8 comments Continue reading

Eaton’s other reagents

On Friday, I found myself discussing the use of Eaton's reagent with a coworker. Many people know it as a handy alternative to polyphosphoric acid (PPA) for acylations, Friedel-Crafts reactions and the like. It's even endorsed by Milkshake. A simple 7.7 wt% solution of phosphorus pentoxide in methanesulfonic acid, it's not as viscid, viscous or  unpleasant to work up as PPA.[1] And it's commercially available. But neither my coworker, nor many other people I know, are aware of Eaton's other contributions to the synthetic world. He's still an emeritus professor at the University of Chicago, and you can read about his interests on his website, but what he's most famous for, unbeknownst to many younger chemists, is his synthesis of the cubanes.

Filed under: Lab, Serious, Total Synthesis | 25,439 views | 6 comments Continue reading

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.

Filed under: Named reactions, Serious | 14,994 views | 2 comments Continue reading

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 | 34,005 views | 7 comments 6 Comments