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Derek Lowe The 2002 Model

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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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February 6, 2013

Anyone Still Swimming in the Chiral Pool?

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Posted by Derek

My grad school work was chiral-pool synthesis; trying to make a complex natural product from carbohydrate starting materials. There was quite a bit of that around in those days, but you have to wonder about its place in the world by now. It's true that everyone likes to be able to buy their chiral centers, especially if they're from the naturally-occuring series (nobody's keen to use L-glucose as their starting material if they can avoid it!) We certainly love to do that in the drug industry, and we can often get away with such syntheses, since our compounds generally don't have too many chiral centers.

But how developed are the multicenter methods? I certainly did not enjoy manipulating the multiple chiral centers on a sugar molecule, although you can (with care and attention) do some interesting gymnastics on that framework. But I think that asymmetric synthesis, especially catalytic variations, is more widely used today to build things up, rather than starting with a lot of chirality and working it around to what you want. The synthetic difficulties of that latter method often seem to get out of hand, and the methods aren't as general as the build-up-your-chirality ones.

Is my impression correct? And if so, is this the way things should be? My tendency is to say "yes" to both questions, but I'd like to see what the general opinions are.

Comments (17) + TrackBacks (0) | Category: Chemical News | Natural Products


1. Irondoc on February 6, 2013 1:03 PM writes...

Us chemists in the nucleic acid analog/oligonucleotide chemistry world are still swimming in this pool. A common joke is to say that our starting material is corn (glucose). Allofuranose, xylose, glucose, are all our friends!

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2. Boghog on February 6, 2013 1:19 PM writes...

With apologizes to Derek, Danishefsky once referred to it as the chiral cesspool ;-)

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3. Am I Lloyd on February 6, 2013 1:42 PM writes...

Another way to ask the question in the title would be, "Does Hanessian's work still mean much"?

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4. anon on February 6, 2013 1:53 PM writes...

The Baran group seems to utilize the chiral pool whenever feasible for natural product synthesis. But they do use asymmetric catalyst to begin routes too. They're also not above making racemates. So I guess their not swimming in the pool non-stop, but more dipping the toes in when it suits them.

I think their (-)-fischerindole synthesis began with carvone oxide.

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5. Cosmo Kramer on February 6, 2013 2:09 PM writes...

Back in the day, we used to refer to the syntheses Derek refers to as "carbo-grinding."

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6. milkshake on February 6, 2013 2:44 PM writes...

Depends how fast and cheap you want your building blocks. If you are in business of synthesizing 1 mg of marine monster, just enough so that you can take carbon NMR spectra, write up and graduate, you will pick the quickest easiest route to your building blocks and have the grant agency worry about the costs. But if you are in a pharma process group optimizing a synthetic route into a scalable practical process, you will probably spend a lot of time trying to optimize methodology for the building blocks. Asymmetric transformations are great but you first need to develop assay fpor ee and you may then spend several months just testing commercially available ligands/metal pre-catalysts/additives for one synthetic step

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7. Anonymous on February 6, 2013 3:40 PM writes...

Long but elegant.

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8. will on February 6, 2013 4:26 PM writes...

Is (R)/(S) epichlorohydrin produced asymetrically or from a glyceraldehyde or the like.

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9. anon on February 6, 2013 5:27 PM writes...

My advisor called all syntheses that used glucose or something similar and went through all sorts of gyrations to get a useful chiral starting material as

"yet another rape of a sugar"

Most chiral centers in pharma projects these days seem to arise by CBS reductions, Noyori hydrogenations, etc. rather than such steppy routes. But there are not so many natural product-like development candidates with tons of stereocenters, either, unless you're at a place like Eisai.

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10. milkshake on February 6, 2013 5:43 PM writes...

@8: small mono-substituted oxiranes such as epichlorohydrine are nowadays produced in bulk scale from racemate by asymmetric hydrolysis in the presence of chiral Jacobsen salene catalyst, with 0.55 eq. of water. It is very cheap to do even though you burn away 50-55% of the material because the racemic epoxide costs almost nothing, the catalyst is very cheap and easy to make too, you can run the hydrolysis without solvent at room temp or below, and distilling the leftover optically epoxide away from the diol (and the catalyst) is pretty easy as long as the substituent is reasonably small

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11. Nylarg on February 6, 2013 8:14 PM writes...

The heyday of sugar chemistry is long over, carbohydrates are now a poor choice in a world where commercial sources of chirality are becoming that much easier to obtain.

When setting out to do total synthesis you ideally want to go from a known source of chirality so you don't have to redevelop a reaction and analysis system.

Chiral pool will always be the easiest option, followed by chiral chemicals which can be made by literature precedence.

After that, there are only a handful of robust assymetric reactions with good substrate scope.

The research group I am in does a lot of work with enzymatically derived chemicals, in truth we order the stuff by the kilo from a company in Scotland because purifying anything from 10 litres of fermentation broth is an excruciating task.

The more we develop asymmetric chemistry, the easier it will be to obtain decent chiral starting materials.

As for multiple stereocentres, you only need to establish chirality once. Diastereoselectivity is far far easier than enantioselectivity.

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12. anon95 on February 6, 2013 9:31 PM writes...

is there an asymmetric method which will give exclusively a single enantiomer, I did not think so. Chiral pool approach will certainely provide a single isomer of choice

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13. eugene on February 7, 2013 5:53 AM writes...

I worked in a place where chiral synthesis was important about ten years ago, but our compounds only had 2 or 3 stereocenters once and often they were pretty isolated so multiple stereocenter synthesis would be not applicable to that with current methods. We often started with achiral building blocks and introduced chirality via enzyme resolution of an alcohol (and then column) or Sharpless epoxidation. I still get papers from them to look at from time to time, and it seems methods have not changed much.

Like Nylarg says, diastereomer separation really helped out, but not that often. There were a lot of epic columns that I remember that separated things with really close polarity profiles.

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14. Anonymous on February 8, 2013 1:18 AM writes...

My old group used to hedge its bets and use a lot of enantioselective biotransformations. Such as converting toluene to a cis diol with TDO.

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15. Anon on February 8, 2013 8:35 AM writes...

My former advisor was an editorial nitpicker and DESPISED the term chiral pool. As he would put it "It is the pool of chiral starting materials, the pool itself is not chiral". I heard it so much that I now pass it along to my students.

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16. Easwar on April 13, 2013 2:26 PM writes...

Can someone clarify this for me? Suppose I carry out the total synthesis of a natural product with just one chiral centre, starting from a chiral source. I introduce the desired chiral centre in the natural product and then destroy the original one I started with. Would it still be justified to call the synthesis "enantioselective total synthesis of XYZ"? or should it be "synthesis of enantiopure XYZ via diastereoselective protocol"? Kindly clarify

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17. on May 31, 2013 10:28 PM writes...

It better be called relay chiral pool synthesis....on a lighter note!

I would just go with "enantioselective total synthesis of XYZ"

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