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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: Twitter: Dereklowe

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November 12, 2012

Unknown Heterocyles: Destined to Remain That Way?

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Posted by Derek

Here's a general organic chemistry question for the crowd, inspired by a recent discussion among colleagues. We were whiteboarding around some structures, and the statement was made that "By this time in the history of organic chemistry, unknown heterocycles are probably unknown for a very good reason". So, true or false? Are the rings that we haven't made yet mostly unmade because they're very hard (or impossible), or mostly because no one's ever cared about them (or realized that they'd made them at all)?

Note that this problem was the subject of some thorough theme-and-variations work a few years ago. That paper would suggest that that as many as 90% of the unknown heterocycles are simply not feasible to make, but that still leaves you with three thousand or so that are. So the answer to the question above might turn out to be "Both at the same time. . ."

Comments (13) + TrackBacks (0) | Category: Chemical News


1. Curious Wavefunction on November 12, 2012 2:46 PM writes...

I am thinking that, at least in some cases, we would start seeing liabilities (solubility, tox etc.) when we introduce more than a few heteroatoms in a ring or move them around in certain patterns. So I would think that at least some of those heteroatom-rich cycles have not been made for good reasons.

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2. Canageek on November 12, 2012 3:09 PM writes...

I think we are going to find a lot more. Someone is going to discover some funky catalyst, and boom, there will be an explosion in the field. Also; there are lots of heterocycles being discovered, just not ones useful for drugs. I found one by accident this summer that has 2 boron, 2 nitrogen and 2 carbon in it. (Sadly, it hasn't been published yet so I can't give details, but it has a really pretty crystal structure.

I know someone who told me someone in his lab had created a heterocycle with 5 elements in it, but I can't remember the details. Other then it wasn't what they were trying to create.

So heterocycles, sure. Organic heterocycles? Possibly. It seems arrogant to think we know everything there is to know about a topic though.

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3. stop on November 12, 2012 4:43 PM writes...


For some reason your comment reminded me of "true heterocycles." Heterocycles in which each atom is a different element.

Useless? But neat!

See: ACIEE 37, 2501 for an example

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4. MTK on November 12, 2012 5:45 PM writes...

I'd say that most unknown heterocycles are going to be in the medium-ring and large-ring class, although I guess smaller rings with other heteroatoms may be lurking out there.

As to why they haven't been discovered I'm definitely of the "we don't care" school, but that certainly would change dramatically if we found a natural example or some biological activity of a synthetic.

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5. dearieme on November 12, 2012 6:17 PM writes...

This reminds me of Dasent's lovely book "Nonexistent Compounds".

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6. SP on November 12, 2012 6:44 PM writes...

This sounds like someone saying, before the development of Pd chemistry, that all the key C-C bond forming reactions are known. Sure, someone might find some obscure ones, but they're unknown for a reason.

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7. Morten G on November 13, 2012 4:08 AM writes...

Looks like a job for that guy who's calculating the size of organic compound space. For so and so many atoms, what are the possible number of compounds? I think he's up to 17 atoms. Is it in Brian Shoichet's lab?

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8. Morten G on November 13, 2012 4:18 AM writes...

Dammit! I didn't click the link. Please ignore my comment, that was stupid. Though if someone else had a crack at listing the unknown heterocycles they might actually publish the list (are structural biologists and small molecule crystallographers the only people who actually release any data?).

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9. iridium on November 13, 2012 4:32 AM writes...

"problem" is the heterocyclic chemistry is not rewarded by high impact journals.

Try to find a nice way to make some new 6-5 fused ring system with a bounch of N and O/S and submit it to a "good" journal...good luck!

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10. UKPI on November 13, 2012 5:21 AM writes...

@7: That's Prof. J.-L. Reymond at Berne.

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11. Mark_cresset on November 13, 2012 11:21 AM writes...

@8: The list of heteroaromatic rings from Pitt et al. have been available for a while: see

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12. Morten G on November 14, 2012 5:28 AM writes...

Thanks! @10 and @11

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13. Chemical Distributor on November 19, 2012 4:36 AM writes...

Looks like a job for that guy who's calculating the size of organic compound space.I found one by accident this summer that has 2 boron but it has a really pretty crystal structure.

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