Here's a question for the organic chemists in the crowd, and not just those in the drug industry, either. Over the last few years, though, there's been a lot of discussion about how drug company compound libraries have too many compounds with too many aromatic rings in them. Here are some examples of just the sort of thing I have in mind. As mentioned here recently, when you look at real day-to-day reactions from the drug labs, you sure do see an awful lot of metal-catalyzed couplings of aryl rings (and the rest of the time seems to be occupied with making amides to link more of them together).
Now, it's worth remembering that some of the studies on this sort of thing have been criticized for stacking the deck. But at the same time, it's undeniable that the proportion of "flat stuff" has been increasing over the years, to the point that several companies seem to be openly worried about the state of their screening collections.
So here's the question: if you're trying to break out of this, and go to more three-dimensional structures with more saturated rings, what are the best ways to do that? The Diels-Alder reaction has come up here as an example of the kind of transformation that doesn't get run so often in drug research, and it has to be noted that it provides you with instant 3-D character in the products. What we could really use are reactions that somehow annulate pyrrolidines or tetrahydropyrans onto other systems in one swoop, or reliably graft on spiro systems where there was a carbonyl, say.
I know that there are some reactions like these out there, but it would be worthwhile, I think, to hear what people think of when they think of making saturated heterocyclic ring systems. Forget the indoles, the quinolines, the pyrazines and the biphenyls: how do you break into the tetrahydropyrans, the homopiperazines, and the saturated 5,5 systems? Embrace the stereochemistry! (This impinges on the topic of natural-product-like scaffolds, too).
My own nomination, for what it's worth, is to use D-glucal as a starting material. If you hydrogenate that double bond, you now have a chiral tetrahydropyran triol, with differential reactivity, ready to be functionalized. Alternatively, you can go after that double bond to make new fused rings, without falling back into making sugars. My carbohydrate-based synthesis PhD work is showing here, but I'm not talking about embarking on a 27-step route to a natural product here (one of those per lifetime is enough, thanks). But I think the potential for library synthesis in this area is underappreciated.