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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Regeneron Expands | Main | Chlorine Trifluoride: Some Empirical Findings »

April 5, 2013

More Reaction Discovery

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Posted by Derek

The reaction discovery field continues to increase its throughput, on ever-smaller amounts of material. (That link has several previous discussions here imbedded in it). The latest report uses laser-assisted mass spec to analyze aliquots (less than a microliter each) of 696 different reactions and controls, pulled directly from the 96-well plates with no purification. That took the MALDI-TOF machine about two hours, in case you're wondering - setting up the experiments definitely took a lot longer (!)

The key to getting this to work was having a pyrene moeity attached to the back end of the substrate(s) for reaction discovery. This serves as a mass spec label - it ionizes very efficiently under the laser conditions, and allows excellent signal/noise coming out of all the other reaction gunk that might be in there. You can monitor the disappearance of the starting material and/or the appearance of new products, as you wish. In this case, the test bed was an electron-rich alkyne starting material, exposed to a variety of reacting partners and various metal catalysts. The screen picked up two previously unknown annulations, which were then optimized in a second round of experiments.

I continue to think that this sort of work has the potential to remake synthetic chemistry. Whenever there's some potential for new reactions to be found (and metal-catalyzed systems are a prime example) these techniques will let us survey the landscape much more quickly. There's no reason to think that we've managed to find even a good fraction of the useful chemistry out there.

Comments (2) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anon on April 6, 2013 6:00 PM writes...

I'm surprised they didn't have solubility problems with that pyrene.

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2. anon the II on April 8, 2013 10:28 AM writes...

This post needs more comments. So here goes. This stuff is rather derivative of the stuff Nuada was trying to do, except that the "Mass Leveler" is a bit more rational. For that reason, it's probably not as good a leveler and so the quantitation isn't as good for a large cross section of reactions. But Nuada and tagging reactions was probably a bad idea to start with. "Reaction discovery" techniques should have grown naturally from the comby movement. But it was largely thrown out with the whole lot along with a lot of snarky grumbling. Also, I suspect that analyzing with LC/MS along with a (CLND) nitrogen detector would provide a lot more info along with the quantitation without a huge cost in analysis time. I believe that the methodology to do this kind of thing better existed 10 years ago and got tossed out with the whole comby thing and a lot of chemists.

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