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November 25, 2007
You Do The Easy Stuff; I'll Do the Easier
A reader from inside the industry writes:
How is 'what's made' influenced by the synthetic knowledge of the individual med chemist? I would guess that with all the pressure on targets that you've written about, there must be some level of sub-conscious selection based on ease of synthesis, so the difficult structures either never get made or get made later. . .(but) difficulty is a subjective term. The better the chemist the more molecules fall into the easy category. . .
. . .One thing I've noticed is the explosion in bi-aryls since the Suzuki and related chemistry came along. Is this due to a sudden realsiation that bi-aryls could be good molecules or is it due to the fact that Suzuki chemistry is easy?
I've wondered about this one myself, as have many other chemists I've known. It's true that as synthetic chemists we tend to go for the low-hanging fruit; I don't think that anyone could deny it. And that's largely due to pressure to produce results, although I wouldn't rule out laziness, either (never rule out laziness).
But you can often get pretty interesting things to happen by doing simple reactions and small changes. Think about the number of times you've seen activities totally altered by one methyl group, or the metabolic problems that have been fixed by adding a para-fluoro. We don't feel as much need to move into new territory as we might.
As for variation between individual chemists, that's why you want to hire a set of people with diverse backgrounds. (And no, I don't mean HR-style diversity, I mean chemical and scientific diversity). The literature is big enough and varied enough so that people can have a lot of experience and still not overlap with their colleagues much in their favorite reactions and structures. People will still go for the easy stuff, but with any luck there will be enough different definitions of "easy stuff" to keep people from piling up too much.
But I think that this factor isn't quite as big as it used to be, what with the advent of modern literature searching. People can pull out all sorts of reactions from the literature and give 'em a try - it's hard to remember that it used to be quite a bit harder to do that. So what do my industrial readers think - do we just make the easy stuff? If we do, is that a problem? How much is "easy" a function of who's doing the chemistry? And has that changed over time?
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