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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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« Update on Bexarotene for Alzheimer's | Main | Check Out These Molecules »

May 30, 2013

Making the Non-Flat, Non-Aromatic Compounds

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Posted by Derek

Here's a question for the organic chemists in the crowd, and not just those in the drug industry, either. Over the last few years, though, there's been a lot of discussion about how drug company compound libraries have too many compounds with too many aromatic rings in them. Here are some examples of just the sort of thing I have in mind. As mentioned here recently, when you look at real day-to-day reactions from the drug labs, you sure do see an awful lot of metal-catalyzed couplings of aryl rings (and the rest of the time seems to be occupied with making amides to link more of them together).

Now, it's worth remembering that some of the studies on this sort of thing have been criticized for stacking the deck. But at the same time, it's undeniable that the proportion of "flat stuff" has been increasing over the years, to the point that several companies seem to be openly worried about the state of their screening collections.

So here's the question: if you're trying to break out of this, and go to more three-dimensional structures with more saturated rings, what are the best ways to do that? The Diels-Alder reaction has come up here as an example of the kind of transformation that doesn't get run so often in drug research, and it has to be noted that it provides you with instant 3-D character in the products. What we could really use are reactions that somehow annulate pyrrolidines or tetrahydropyrans onto other systems in one swoop, or reliably graft on spiro systems where there was a carbonyl, say.

I know that there are some reactions like these out there, but it would be worthwhile, I think, to hear what people think of when they think of making saturated heterocyclic ring systems. Forget the indoles, the quinolines, the pyrazines and the biphenyls: how do you break into the tetrahydropyrans, the homopiperazines, and the saturated 5,5 systems? Embrace the stereochemistry! (This impinges on the topic of natural-product-like scaffolds, too).

My own nomination, for what it's worth, is to use D-glucal as a starting material. If you hydrogenate that double bond, you now have a chiral tetrahydropyran triol, with differential reactivity, ready to be functionalized. Alternatively, you can go after that double bond to make new fused rings, without falling back into making sugars. My carbohydrate-based synthesis PhD work is showing here, but I'm not talking about embarking on a 27-step route to a natural product here (one of those per lifetime is enough, thanks). But I think the potential for library synthesis in this area is underappreciated.

Comments (40) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


1. ClutchChemist on May 30, 2013 9:55 AM writes...

I'm not a medicinal chemist at all, but does anyone who does this kind of work make oxazolidines from ketones and ethanolamines? No chirality control in the product, which might kill the idea, but you get an interesting spiro center and an amine that you can further functionalize.

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2. luysii on May 30, 2013 10:06 AM writes...

Do not assume that aromatic rings in proteins are flat. There are (at least) 19 proteins where this isn’t the case for the 6 membered rings of phenylalanine or tyrosine. A truly fascinating paper [ Proc. Natl. Acad. Sci. vol. 109 pp. 9414 - 9419 '12 ] describes alpha-lytic protease (alphaLP from here on) in which phenylalanine #228 has a bent benzene ring. Even more interestingly, this raises the energy of the protein and appears to be an integral part of the protein’s biological functioning. So it’s not an accident.

Perhaps this is true for some of our drugs as well (but I doubt it).

For more details please see

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3. Toad on May 30, 2013 10:08 AM writes...

I was always enamored with the [3+2] cycloaddition reactions, especially of azomethine ylides, to give elaborately functionalized pyrrolidines and the like. I remember a very nice talk by Bartlett years ago that demonstrated a large variety of substituted and fused examples. I don't see much in that area these days, but do know there has been work on the asymmetric and/or catalytic syntheses of such.

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4. CMCguy on May 30, 2013 10:13 AM writes...

I would agree in general that most chemical libraries probably do contain an overabundance of flat aromatic compounds that is largely attributable to a couple main factors: ease (familiarity) of construction and availability of analogs with "diverse" functionality. Suzuki couplings and similar reactions are generally well-behaved and widely implementable to a successful compound prep (or at least require minimal refinement). These reaction became a rage when first introduced and it was amazing how many people integrated in to PhD thesis work (even sometime where appears a force fit), if you took a survey of Syn chemist I would suspect it would be rare to find those who have not applied metal-catalyzed couplings at some point.

As far as raw materials most people want or need to buy only what the chemical catalogs sell and there are just so many benzene analogs plus a few series heterocylic compounds with accessible functionality to select from. I do not really follow what is out there today but back in the Combichem days we intentionally sought out inputs to provide more 3D character and found very limited choices (and many of those would act as grease-balls).

My impression is that everyone in DD recognizes these factors and would really like to try to get more out of the box however with strong countervailing demand to move projects along faster and faster there is little tolerance for activity that might indeed expand chemical nature of library but can not overcome the poor probability of hitting a target. CAD was/is supposed to aid 3D thought processes but again sometime modeling info and chemistry that can actually do are hard to connect.

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5. Hap on May 30, 2013 10:15 AM writes...

I wonder if N-benzylglycine and aryl aldehydes would undergo [3+2] with D-glucal - that would get you pyranopyrrolidines with diversity and some room for functionalization, and lots of stereochemistry. (You could also cleave the benzyl group to acylate or alkylate on N).

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6. weirdo on May 30, 2013 10:24 AM writes...

Organocatalytic multi-component reactions anyone?

Sounds like a good idea for a company.

Based in Princeton.

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7. somewhat relevant on May 30, 2013 10:31 AM writes...

The Broad has made a few libraries from Glucal and Galactal building blocks.

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8. Anonymous on May 30, 2013 10:32 AM writes...

One thing to think about is how to get substituents into axial positions with minimal steric footprint.

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9. eugene on May 30, 2013 10:44 AM writes...

You could probably make big rings with olefin metathesis and then do stereoselective hydrogenation, but that still hasn't been developed so well, so maybe followed by Sharpless epoxidation if an alcohol is nearby or use some enzyme?

Wouldn't making stuff less aromatic mean that it would be a lot more greasy and thus not what you drug guys want? Well, I'm not a medicinal chemist, but when we had to make these linear compounds with a few stereocenters on them and functional groups (but mostly just a carbon chain), we would do Wittig coupling. A lot of Wittig coupling.

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10. followerchemist on May 30, 2013 10:53 AM writes...

Saw Cubanes being used recently as analogues of aromatics (such as aniline, but without the associated toxicity apparently) the compounds weren't chiral, but cubanes aren't exactly flat either!

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11. Project Osprey on May 30, 2013 11:11 AM writes...

What about oxazolines? Simple, stable, hard NOT to make enantiopure.

Btw if you want a weird way of turning a carbonyl into a spiro-ring: how about converting it into a cyclopropyl group with a modified Tebbe's reagent

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12. Ed on May 30, 2013 11:21 AM writes...

It is fairly straightforward to hydrogenate substituted pyridines to give all sorts of exotic piperidines. Telescoping with Boc protection can often give separable mixtures of easily handled compounds, I used platinum oxide, c.H2SO4, IPA with balloon pressures of hydrogen.

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13. pharma professional on May 30, 2013 12:09 PM writes...

Consider the following:

Thermally induced ring expansions of substituted cyclobutenones derived from squaric acid - can get to a number of substituted saturated ring systems this way, taking advantage of the alleviation of strain in 4-membered rings.

Cyclization of funtionalized amino acids. AAs are commercially available in enantiopure form, and have well known protection-deprotection-activation chemistry. It's not exciting or new - just an 'old school' way of getting to many saturated chiral heterocycles with good stereocontrol.

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14. NotAChemist on May 30, 2013 12:33 PM writes...

Not very familiar with organic chemistry. I do know that one can change the position of a double bond within an olefin using a platinum catalyst. Perhaps one can manipulate the position of the double bonds in higher carbon number olefins to control where the Diels-Alder reaction performs its addition. Would this be fighting a loosing battle with Gibbs and his "free" energy?

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15. newnickname on May 30, 2013 12:43 PM writes...

You are asking more for reactions than structures, but I'll ignore that. I like "cleft" molecules. Troger's Base, Kagan's Ether, Kemp's Acid et cetera. They orient substituents in such a way that you can imagine them interacting with a single epitope. And you can still get a lot of diversity with simple chemistry.

For non-organickers reading this blog, it's kind of like picturing the "flat" molecules this topic is about as a planar (2 dimensional) clockface with attachments at 12, 4 and 8 sticking straight out and still in the plane; they cannot easily converge and interact with a straight line (surface) of a protein target all at once.

Cleft molecules can have multiple, variable groups all oriented in the same general direction. I'll use the analogy of a squid with its tentacles all pointing in the same general direction and ready to grab hold of a target (epitope) and not let go. Chemically, Troger's Base, etc. are squid bodies and we can attach different tentacles with fairly reasonable chemical methods.

Admittedly, Troger's Base and Kagan's Ether contain big "flat" (planar) pieces but the linking groups force the whole structure to be non-planar, chiral and oriented.

I think clefts were underutilized in combichem. I think there was only one publication on a small Kemp Acid library (out of Selectide Corp).

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16. MoMo on May 30, 2013 2:03 PM writes...

Trogers base? Kagan's ether, Kemp's Acid? what's next Edie's Amine? The polyfunctional amine for dictatorial molecules?

Ed, you should continue on this work, the other scaffolds will only hurt and damage biological membranes as proven in the past, but Amines will set you free!

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17. iridium on May 30, 2013 2:30 PM writes...


are you serious??

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18. PharmaHeretic on May 30, 2013 3:28 PM writes...

Talking about compounds with multiple aromatic rings and their reactions...


First-ever high-resolution images of a molecule as it breaks and reforms chemical bonds

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19. milkshake on May 30, 2013 3:35 PM writes...

lovely-to-run and somewhat underutilized are cyclizations leading to benzopyranes (aka chromanes): o-hydroxyacetophenone + a cyclic reactive ketone such as N-acetyl-4-piperidone + few drops of pyrrolidine, reflux in MeOH = spiro chromanone.

2-hydroxybenzaldehyde + acrylonitrile + DABCO in MeOH = 2-H chromene-carbonitrile

Another lovely source for diversity oriented parallel synthesis would be inexpensive natural mono and diterpenoids

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20. Anonymous on May 30, 2013 8:48 PM writes...

Another way to make carbocycles is transition-metal-catalyzed [2+2+2] cycloaddition reactions of alkenes with allenes, alkynes, or other alkenes. Some degrees of unsaturation will be left in the product depending on the substrates used. Also, the possibility exists to do the reaction enantioselectively with chiral ligands.

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21. Nerd v Geek on May 30, 2013 10:34 PM writes...

I've always liked acetal/ketal formation as a simple way of introducing 3-dimensionality. Obviously acid stability can be an issue but those from catechols are quite stable, and back-in-the-day RPR had a MAP kinase inhibitor with a cyclic acetal ( (Not sure if it went anywhere but that could be because it was a MAP kinase inhibitor!)

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22. PharmaHeretic on May 30, 2013 11:49 PM writes...

DPP-4 inhibitors and Incretin mimics under scrutiny.

A Lone Voice Raises Alarms on Lucrative Diabetes Drugs

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23. Stephen on May 31, 2013 6:19 AM writes...

I think that Krische's hydrogenative C-C coupling is a very simple and quick way to build polyketide-like aliphatic stereocenters.
Org. Process Res. Dev., 2011, 15, 1236–1242.
DOI: 10.1021/op200195m

From personal experience, these are much easier than using Evans aldol methodology or running Brown/Roush crotylations. And as far as scaling up, we certainly (domestically) have the excess batch capacity that would be kinetically required.

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24. Bunsen Honeydew on May 31, 2013 7:56 AM writes...

I like the idea of chiral pool materials, especially sugars, modified by enzymes such as hydrolases to do selective (de)protections.

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25. GladToMoveToProcess on May 31, 2013 9:17 AM writes...

Milkshake (19) mentioned starting with terpenoids. That leads to the possibility of carbocation rearrangements. One can imagine attaching some "pharmaceutically interesting" groups, then rearranging the terpenoids to all sorts of wild structures. Not necessarily predictable what would come out, but could give lots of "diversity" in short order. The flavor and fragrance folks do this a lot; of course, they don't have to worry about the acidic conditions ruining their functionality!

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26. neo on May 31, 2013 10:57 AM writes...

Derek, I came from the same labs as you (my favorite was galactal). I've wasted the first decade and a half of my career on such noble pursuits as introducing three dimensionality into my molecules, and whithout exception have been dominated in every respect by those whose idea of science is to purchase aromatic tinker-toys and stitch them together with palladium to make high affinity ligands. Of course the projects all failed, but those who made the most potent compounds were rewarded. My work has always been looked on as promising, but months behind.

My advice to anyone actually tempted to follow up any of the discussion on this post, is to stop listening to what management says, and watch what they do.

So, I've learned my lesson. I'm off to do another Suzuki...

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27. Yancey Ward on June 1, 2013 11:15 AM writes...

My last year as a med chemist, we were required to offer up ideas for general library syntheses. I offered up three different ideas based on work I was doing for a project at the time that provided exactly these sorts of highly 3D structures. I had even demonstrated that they actually worked quite well, and they were not selected.

I have to say, I agree with Neo just above. Don't believe a thing management tells you.

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28. Spokoyny on June 3, 2013 3:10 PM writes...

Icosahedral carboranes are great 3D pharmacophores, and very little work has been done in evaluating these species in pharma.

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29. srp on June 6, 2013 8:22 PM writes...

So are the experiences of neo and Yancey caused by the "suits" or by the science supervisors? Many MBAs would be easily snowed by even a fallacious argument for 3D presented with conviction ("It has one more dimension so it's 50% better so I should get more credit for each one I do.")

I suspect that the culprits must be on the science side.

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30. Paul on June 29, 2013 5:42 AM writes...

My favourite is nitrile oxide cycloaddition on exocyclic methylene compounds - instant heterocyclic spiro compounds.

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31. Tarko laszlo on July 18, 2013 3:45 AM writes...

Regarding aromaticity concept see

Aromatic molecular zones and fragments
L. Tarko
ARKIVOC, 2008, Part xi, p. 24 – 45

DESCRIPT software can compute aromaticiy, non-aromaticity and anti-aromaticity for any thinkable structures.

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