A comment to yesterday's post made a point that seemed instantly familiar, but it's one that my own thoughts had never quite put together. All of us who do medicinal chemistry came out of academic labs; that's where you get the degrees you need to have to be hired. Many of us worked on the synthesis of complex molecules for those degrees, since that's traditionally been a preferred base for drug companies to hire from. (You get a lot of experience of different kinds of reactions that way, have to deal with setbacks and adversity, and have to learn to think for yourself. Plus, if you can put up with some of the people who do natural products synthesis, the thinking goes, you can put up with anything).
Here's the interesting part, though. People who do the glass-filament spiderweb-sculpture work that is total natural product synthesis will defend it on many grounds (some more defensible than others, in my view). They have, naturally enough, a bias in favor of that kind of work. But have those of us who've done that kind of chemistry and then moved on to industry ended up with the opposite bias? Have we reacted against the forced-march experience of some of our early training by resolving never to get stuck in such a situation again (which is reasonable), but at the same time resolved never to get stuck doing fancy synthesis again?
That one may not be so reasonable. And I don't mean that we avoid twenty-step syntheses for irrational reasons, because there are perfectly rational reasons for fleeing from such things in industrial work. But this bias might extend further. Take a workhorse reaction like palladium-catalyzed coupling - that's just what people tend to think of when they think of uninspiring industrial organic synthesis, two or three lumpy heteroaromatics stuck together with Suzuki couplings, yawn. One of my colleagues, though, recently mentioned that he saw too many people sticking with rather primitive conditions for such reactions and taking their 50% yields (and cleanup problems) as just the normal course of events. And he's got a point, I'd say. There really are better conditions to use as your default Pd coupling mixture than the ones from the mid-1990s. You don't have to always clean all the red-brown gunk out from your product after using (dppf) as your phosphine ligand, and good ol' tetrakis is not always the reagent of choice. But a lot of people just take the standard brew, throw their starting materials in there, and bang 'em together. Crank up the microwave some more if it doesn't work.
I can see how this happens. After all, the big point that people have to learn when they join a drug research effort is that chemistry is not an end in itself - it's a tool to make compounds for another end entirely. If you're just making analogs in the early stages of a new project, no one's going to care much if your yields are low, because the key thing is that you made the compounds. I've said myself (many times) that there are two yield in medicinal chemistry: enough, and not enough. Often, perhaps a little too often, five milligrams qualifies as "enough", which means that you can check off a box through some really brutal chemistry.
But at the same time, if you could make simple changes to your reaction conditions, or to the kinds of reactions you tend to run, you could potentially make more compounds (because you're not spending so much time cleaning them up), make them in higher yields (or make your limited amount of starting material stretch further), or make more interesting (and patentable) ones, too. I think that too many of us do tend to get stuck in synthetic ruts of various sorts.
Perhaps the main cause of this is the pressure of normal drug discovery work. But I do have to wonder if some of the problem is a bit of aversion to the latest, hottest reagent or technique coming out of the academic labs. To be sure, a lot of that stuff isn't so useful out here in what it pleases us to call the real world. But there are a lot of things we could stand to learn, as well. Palladium couplings used to be considered kind of out-there, too, you know. . .