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!