Over at Chemistry Blog, there's a post by Quintus on the synthesis of a complex natural product, FR-182877. The route is interesting in that it features a key Diels-Alder reaction, and the post mentions that this isn't a reaction that gets used much in industry.
True enough - that one and the Claisen rearrangement are the first reactions I think of in the category of "taught in every organic chemistry course, haven't run one in years". In the case of the Claisen, the number of years is now getting up to. . .hmm, about 26, I think. The Diels-Alder has shown up a bit more often for me, and someone in my lab was running one last year, but it was the first time she'd ever done it (after many years of drug discovery experience).
Why is that? The post I linked to suggested a good reason that one isn't done too often on scale: it can be unpredictably exothermic, and some of the reactants can decide to polymerize instead, which you don't want, either. That can be very exothermic, too, and leaves you with a reactor full of useless plastic gunk which will have to be removed with tools ranging from a scoop to a saw. This is a good time to adduce the benefits of flow chemistry, which has been successfully applied in such cases, and is worth thinking about any time you have a batch reaction that might take off on you.
But to scale something up, you need to have an interest in that structure to start with. There's another reason that you don't see so many Diels-Alders in drug synthesis, and it has to do with the sorts of molecules we tend to make. The cycloaddition gives you a three-dimensional structure with stereocenters, and medicinal chemistry, notoriously, tends to favor flat aromatic rings, sometimes very much to its detriment. Many drug discovery departments have taken the pledge over the years to try to cut back on the flatness and introduce more sp3 carbons, but it doesn't always take. (For one thing, if your leads are coming out of your screening collection, odds are you'll be starting with something on the flat end of the scale, because that's what your past projects filled the files with).
I think that fragment-based drug discovery has a better chance of giving you 3-D leads, but only if you pay attention while you're working on it. Those hits can sometimes be prosecuted in the flat-and-aryl style, too, if you insist. And I think it's fair to say that a lot of fragment hits have an aryl (especially a heteroaryl) ring in them, which might reflect the ease of assembling a fragment-sized library of compounds full of such. Even the fragment folks have been talking over the years about the need to get more three-dimensionality into the collections, and vendors have been pitching this as a feature of their offerings.
The other rap on the classic Diels-Alder reaction is that it gives you substituted cyclohexanes, which aren't always the first place you look for drug leads. But the hetero-Diels-Alder reactions can give you a lot of interesting compounds that look more drug-like, and I think that they deserve more play than they get in this business. I'll go ahead and take a public pledge to run a series of them before the year is out!
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
1. Pete on August 24, 2012 8:29 AM writes...
We really shouldn't be talking about aromatic rings as flat (van der Waals died almost 90 years ago) and it would be more appropriate to describe them as of constant thickness. It's worth taking a really close look at some of the analysis presented in support of the view that too many aromatic rings are bad. One issue is that number of aromatic rings is likely to be strongly correlated with molecular weight.
Back in the late 1980s, I used Diels Alder reactions to to actually make aromatic rings from isobenzofurans. The adducts were a lot more easily handled than the final products which were obtained by dehydration of the adducts. This is somewhat ironic given that my first Diels Alder reaction (run as a second year undergrad) was an unmitigated disaster.
Permalink to Comment2. A-non-moose on August 24, 2012 8:58 AM writes...
When you say industry, you mean pharma, right? The F&F industry use claisen and DA reactions all the time.
Permalink to Comment3. WCA on August 24, 2012 9:03 AM writes...
Cracking cyclopentadiene is a lost art.
Permalink to Comment4. Will on August 24, 2012 9:35 AM writes...
Burprenorphine and its congeners and various steroid based drugs seem candidates for DA types reactions
Permalink to Comment5. a-non-moose on August 24, 2012 10:07 AM writes...
@3, funny, I am doing that right now. It is noice to see a distillate of 42C coming from the reactor.
Permalink to Comment6. Grignard on August 24, 2012 10:21 AM writes...
Agrochemical industry is applying it on a routine basis for increasingly complicated structures. You can build up a furan (resmethrin)in an elegant manner. Along these lines, the Vitamin B6 synthesis via a DA can be an inspiration to build up a pyridine when more classical reactions fail.
Permalink to Comment7. Chemjobber on August 24, 2012 10:34 AM writes...
How does one kill the awful, pungent odor of cyclopentadiene?
Permalink to Comment8. Pete on August 24, 2012 10:44 AM writes...
Make it react with a dienophile that smells even worse?
Permalink to Comment9. Grignard on August 24, 2012 2:13 PM writes...
#7: for small spillages or pre-rinse maleic anhydride does a rapid and clean job.
Permalink to Comment10. Rickert on August 24, 2012 2:24 PM writes...
Did the grand old industry veterans in pharma apply the Diels-Alder reaction more often in the heyday of prostaglandin synthesis - catalyzed by the Nobel prize for Otto Diels and Kurt Alder in 1950? Was there a "hype" to apply this reaction, similar to the current cross-coupling-of-flat-molecules trend?
Permalink to Comment11. barry on August 24, 2012 3:04 PM writes...
of course counting Sp3 carbons is only a rough measure of flatness. E.g. Bi(napth) and helicene are far from flat
Permalink to Comment12. Anonymous on August 24, 2012 10:16 PM writes...
We are using a DA on commercial scale. Sets several chiral centers in one single step - an thing of beauty.
Permalink to Comment13. newnickname on August 25, 2012 10:39 AM writes...
One of the best and classic reference works on the topic: Diene Synthesis by A.S. Onischenko (1964).
Onischenko mal y pense.
Permalink to Comment14. RD on August 27, 2012 12:54 AM writes...
#3, #5: Storytime - my first ever lab accident in undergrad came when cracking cyclopentadiene. I totally ignored the lab manual's advice to use a large flask and a small flame, deciding that a small flask and a large flame would be much quicker, so that when I got distracted by a classmate I wound up setting fire to the cotton wool around the outside of the fractionating column. Took me ages to scrub that clean. Those were the days.
Permalink to Comment15. Free Radical on August 27, 2012 6:36 AM writes...
I find it interesting that Corey has stated that:
"If one chemical reaction had to be selected from all those in the repertoire of synthetic organic chemists as the most useful and powerful synthetic construction, it was clear by 1970 that the Diels-Alder reaction would be the logical choice." (Angew. review in 2002).
yet modern MedChemists barely use it. (Not saying academics and industrialists should have the same aims, but Corey didn't limit his statement to academics...).
Makes me wonder what "one reaction" is most important for MedChem. Pd-cat. I guess? Suzuki? Buchwald-Hartwig?
Just sayin...
Permalink to Comment16. overthetop on August 27, 2012 8:40 AM writes...
We don't run Diels-Alder type reactions very often because the vast majority of the time we can just buy our starting material from somewhere. It's generally cheaper and saves time that way. When the desired starting material isn't available, often times we will first try and rework the route from some other commercially available starting material. If that isn't possible, then we do the DA reaction.
Permalink to Comment17. Grignard on August 28, 2012 10:31 AM writes...
A nice example how the improved synthetic access to a DA product triggered great research can be found in the vince lactam story by Robert Vince. Our Medicinal Chemists use the DA a lot.
Chem. Rev. 2012, 112, 4642: "Our modifications to the protocol helped prepare the lactam at scales as large as 200 g. This proved to be a highly beneficial development and led to the preparation of carbocyclic nucleosides for the first time via a simple and high yielding preparative route [...]. These developments prompted an increase in the interest of research community in the lactam and the chemistry related to it, and subsequently led to the rapid acceptance of carbocyclic nucleoside as medicinal agents of high efficacy. It is noteworthy that this preparative protocol was performed without the use of any special equipment in our academic laboratorial settings."
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