I’ve been doing plenty of bench chemistry lately, but I sometimes wonder what my earlier self would have thought about it. Not the fact of still doing chemistry at the bench this late in my career – I would have applauded that! But I’m wondering more about the kinds of reactions that I do.
When I was in graduate school, I was doing total synthesis of a natural product, and that sort of work can turn into an ‘any weapon to hand’ situation. It was not as straightforward a synthesis as we had planned out, because let’s face it, no total synthesis ever is. I had to retool several times, backing up a few steps because I found myself facing unexpected dead ends. The tricky part is not letting these detours add more steps to the plan. There’s constant tension in this sort of research between producing an elegant synthesis and just getting something (anything!) to work. But ‘just make it work’ usually produces long, steppy, pedestrian routes.
I certainly did a wide variety of chemistry in those years, as I scrambled to find my way through to the final product. There are several reaction types in my PhD dissertation that I have never had occasion to run again, even after a further 40 years in the lab! Afterwards, in my postdoc, I found myself doing free radical work – an area new to me, and I haven’t had many chances to revisit the sorts of reactions that I was doing then, either. That’s because the next phase of my career took me into medicinal chemistry research in the pharmaceutical industry.
And there, famously, many a hotshot organic synthetic chemist suddenly finds (perhaps to their shock) that a lot of simple reaction types from their undergraduate organic textbooks come back into their lives. That is, of course, because those classics tend to work over a wide variety of starting material structures. In drug discovery research, you start to realise that your definition of elegance in chemistry needs to change. You’re there to make a lot of compounds as quickly as you can manage, variations on the themes of the lead structures of whatever project you’re on at the time. Reactions and pathways that let you turn out a lot of those variations are elegant, no matter how hammer-and-tongs the bench chemistry may be. Even low yields are no barrier to success – as I’m fond of saying, there are only two yields in early-stage med-chem: enough and not enough.
In drug discovery research, you start to realise that your definition of elegance in chemistry needs to change
But at the same time, medicinal chemists are willing to try almost anything that promises to assemble interesting structures quickly. So you’ll see redox photochemistry, exotic metal-catalysed couplings, electrochemistry, and whatever other interesting reactions showed up in literature searches. I spent quite a few years in this style of work, and it will keep you on your scientific toes.
Now, though, I’m working on some unusual chemical biology ideas. The molecules I’m making certainly look odd, and they are designed to do some very odd things once they get into cells (such are my hopes). But the reactions I’m using to make them are the most basic, boring chemistry imaginable. The great majority of the reactions I’ve run for the last couple of years have probably been amide couplings, for example, and you don’t get much more boring than that. They suit me just fine, though. The biology I’m targeting is exotic stuff indeed, and the last thing I need is exotic chemistry along the way to it. Intricate chemistry on top of intricate biology would sink my projects for sure, so I’ve made my choice. I think my younger self would understand!
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