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September 17, 2008
Sugars: Still Crazy After All These Years
Posted by Derek
I did carbohydrate chemistry for my PhD - well, I used carbohydrates as starting materials to make other molecules, but I did my share of pure carbohydrate stuff along the way. And although that was over twenty years ago, the stuff I did is still considered by most people to be a sort of esoteric thing, an odd specialty that not many people have experience with. Time has clearly not mainstreamed sugar chemistry.
It's not like people don't use the things, often for just the reasons that I used to (as versatile chiral starting materials). But the reputation of the compounds lingers. I think it's because of all the odd little reactions that sugars do. There's a certain amount of knowledge that has to be learned - all that stuff with the anomeric center, for starters, and all the name reactions that only occur in sugars, like the Ferrier rearrangement.
Then there are the protecting groups. With all those hydroxys hanging around, a lot of them are going to have to be tied up for extended periods while your work gets done. But every hydroxy group on a sugar ring has a slightly different personality - they acylate and deacylate in a particular order, for one thing, which varies from one sugar system to another. And there are the acetals and ketals to tie up two hydroxyls at once - very useful, but there are a lot of different combinations that can form under different conditions and with different carbonyl reactants.
The closest analog to the field that I can think of is steroid chemistry. In its day, that was a hugely popular and important field, with all sorts of ins and outs - tricky transformations that you learned from the old hands. But these days, hardly anyone cares - pure steroid chemistry is a backwater, and many of the esoteric reactions are largely forgotten. Sugar chemistry has escaped that fate - it's still relevant - but hasn't escaped the atmosphere of an eccentric club.
My own sugar knowledge, while still sound, is not exactly up to date. I know that the field has moved on over the years, but I've had only sporadic need to keep up, since carbohydrates don't appear in many drug structures. I've been able to work in some of them once in a while, but I've never worked on a project where my sugar experience has been front and center.
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1. davejac on September 17, 2008 10:31 PM writes...
Funny story, I’m just about to embark on my postgrad career (after my final exam on Monday anyway) into the sugar business. Thanks, and good timing! :D
Permalink to Comment2. eugene on September 17, 2008 10:45 PM writes...
I hear sugar chemistry is very frustrating (apparently a lot more than most other type of small molecule synthesis) and you often end up with black charred remains of baked sugar after many reactions. Or maybe it's all the different protecting groups that drive some people crazy.
Is all this bad press true?
Permalink to Comment3. Handles on September 18, 2008 5:04 AM writes...
Yes, the protecting groups get a little repetitive, but for me the most frustrating thing is having to wait a day or two for your product to lyophilise to dryness, rather than just sticking it on the rotavap. On the plus side, the NMRs keep you on your toes, and you really get to know your Lewis acids.
Permalink to Comment4. Ram on September 18, 2008 5:35 AM writes...
"you really get to know your Lewis acids" is really good one for anybody who worked on carbohydrate chemistry
Permalink to Comment5. Sweet Zombie Jesus on September 18, 2008 7:47 AM writes...
Reminds me of organic chem lecture back in the 70s. K. Barry Sharpless (then an unknown lowly assistant professor who we referred to as B. Very Pointless) was describing the importance of the sense of smell in analytical chemistry. When he was an undergrad in chemistry, he says, he used to go around smelling everything. Some wag behind us whispers "Bicycle seats.". He claims that he was able to identify an unknown during the Stanford grad school entrance practical by burning it. It smelled like caramel, so he knew it was a sugar of some sort.
I wonder what t-butylperoxide smells like?
Permalink to Comment6. NH_chem on September 18, 2008 9:20 AM writes...
I had the joy of working on carbohydrates in grad school for my degree. I learned a huge amount of lab techniques that came in handy when moving into med chem.
Learning how to run flash columns and crystallizing materials were key. TLC was also very useful "back in the day". You gotta love the old H2SO4/EtOH spray and heat the TLC plate.
I had dreams of industry with the hot companies like Glycomed and Isis but the days of carbohydrate based drugs have seemed to gone away with the flavor of the month now being RNAi and Surtuins.
Any carbohydrate chemist can do straight o-chem but it does not translate the other way as easy. Nice blog entry- THANKS!
Permalink to Comment7. Sili on September 18, 2008 9:46 AM writes...
As always, no practical experience from me, but we did (do, presumably) have a biggish group working of anti-sense stuff using their own Locked Nucleic Acids as the backbones.
I only ever solved one or two structures for them because I knew the students from my basic courses - the group as a whole was more enamoured of NMR. Dunno if they've changed now that there's a CCD in-house with a talented young man attached.
Permalink to Comment8. glycochemist on September 18, 2008 9:47 AM writes...
The rumours of the complexity of carbohydrate chemistry are greatly exaggerated.
Permalink to CommentContrary to what Eugene believes we rarely get 'black charred remains', but more often than not nice white powders (many protected monosaccharides can be crystallized, whereas polysaccharides give foams once the last drops of solvents have been removed).
Yes, carbohydrate chemists have to know their orthogonal hydroxyl (and amine) protective groups (acetals in particular), the reactivity of the anomeric center, and a variety of glycosylation methods (Lewis acids) to control alpha/beta linkage formation. I don't think this is too hard to learn.
No special practical skills are required. The handling of deprotected sugars (usually only at the very end of the synthesis) often require ion-exchange in water, but other than that protected sugars are purified on silica in common organic solvents.
In recent years glycochemists have also increasingly used enzymes (glycosyltransferases) to built complex sugars.
9. sticky on September 18, 2008 1:34 PM writes...
Took me a while once to figure out that the powdered sieves I was using were soaking up triflic acid, and my glycosylations were stuck at the ortho ester, kinda hard to tell with a 250 and no LCMS.
Permalink to Comment10. FrankW on September 18, 2008 6:46 PM writes...
I remember Robin Ferrier teaching some of my undergraduate lab classes and lectures. At the time I wondered why there were several in depth labs on carbohydrate chemistry: it seemed a little out of proportion given how quickly sugar chemistry is glossed over in ungergrad chemistry- it later became obvious why the focus on sugars.
He was a really good helpful teacher- and made the chemistry fairly interesting. I feel a little embarrased now, about how little effort I put into that class. Like most undergrads I was more concerned with the chemistry of beer.
Permalink to Comment11. davejac on September 18, 2008 7:27 PM writes...
Good to see more kiwis floating about here! Once my supervisor gets here (he doesn’t take up his position here till the beginning of next year) we’re planning on a trip up to Wellington to see their carbohydrate group, and hopefully we’ll be able to run into Ferrier at some point.
Permalink to Comment12. RTW on September 19, 2008 9:30 AM writes...
At the time the department head at the university I attended was a carbohydrate chemist. Our normal organic lab instructor took ill and our department head filled in. He was a pretty humors fellow and also a Muslum. We where doing a recrystalization, and some having of course more success than others. When one particularly frustrated student successfully got the material to crystalize the professor exclaimed to the class - "What to do do when you do when you see crystalls? Praise Allah and filter!" That was the best line I ever heard, recongnizing the difficulty in later years of acheiving such success when working on some simple sugars, much as Derek using them as starting materials for other things.
On another note about Sharpless using his sense of smell. Well - I once had an interesting discussion with Tomas Hudlicky. Seems his father made a lot of Fluorine sugars and was in the habbit of tasting them. Tomas felt that that experence probably protected his father from all sorts of toxins as he was a very vigourous emeritus professor, playing tennis often with Tomas' grad students!
I personally don't recomend tasting things, but smells sometimes can be useful.
Permalink to Comment13. Tot. Syn. on September 23, 2008 7:29 AM writes...
Plenty of Ferrier rearrangements outside of sugar chemistry; Amos Smith's synthesis of okilactomycin and Danishefsky's work on isomigrastatin both used it. Now the Kiliani ascension - there's a sugars-only reaction. I used to work next to a group that did *loads* of those reactions early in their synthetic routes. The problem was the poor yield and super-stoichiometric sodium cyanide required...
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