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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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June 5, 2013

Quaternary Chiral Centers Made to Order

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Posted by Derek

Chiral catalyst reactions seem to show up on both lists when you talk about new reactions: the list of "Man, we sure do need more of those" and the "If I see one more paper on that I'm going to do something reckless" list.

I sympathize with the latter viewpoint, but the former is closer to reality. What we don't need are more lousy chiral catalyst papers, though, on that I think we can all agree. So I wanted to mention a good one, from Erick Carreira's group at the ETH. They're trying something that we're probably going to be seeing more of in the future: a "dual-catalyst" approach:

In a conceptually different construct aimed at the synthesis of compounds with a pair of stereogenic centers, two chiral catalysts employed concurrently could dictate the configuration of the stereocenters in the product. Ideally, these would operate independently and set both configurations in a single transition state with minimal matched/mismatched interactions. Herein, we report the realization of this concept in the development of a method for the stereodivergent dual-catalytic α-allylation of aldehydes.

Shown is a typical reaction scheme. They're doing iridium-catalysed allylation reactions, which are already known via the work of Hartwig and others, but with a chiral catalyst to activate the nucleophilic end of the reaction and a separate one for the electrophilic end. That lets you more or less dial in the stereocenters you want in the product. It looks like the allyl alcohol need some sort of aryl group, although they can get it to work with a variety of those. The aldehyde component can vary more widely.
Allyl%20reaction.png
You'd expect a scheme like this to have some combinations that work great, but other mismatched ones that struggle a bit. But in this case the yields stay at 60 to 80%, and the ee values are >99% across the board as they switch things around, which is why we're reading this in Science rather than in, well, you can fill in the names of some other journals as well as I can. Making a quaternary chiral center next to a tertiary one in whatever configuration you want is not something you see every day.

I think that chiral multi-catalytic systems will be taking up even more journal pages than ever in the future. It really seems like a way to get things to perform, and there's certainly enough in the idea to keep a lot of people occupied for a long time. Those of us doing drug discovery should resist the urge to flip the pages too quickly, too, because if we really mean all that stuff about making more three-dimensional molecules, we're going to have to do better with chirality than "Run it down an SFC and throw half of it away".

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


COMMENTS

1. Handles on June 5, 2013 10:06 PM writes...

Since they are using iridium, lets hope the people at Planetary Resources get their asteroid mining operation off the ground soon.

Permalink to Comment

2. Mintberry Crunch on June 5, 2013 10:50 PM writes...

1. It's easy to sit and take potshots, but the ability to actually select which diastereomer you would like to make without redesigning the catalyst(s) is a luxury quite hard to come by and as such you are reading this in Science! Obviously someone is going to make this cheaper...

Permalink to Comment

3. Helical_Investor on June 6, 2013 11:16 AM writes...

What we don't need are more lousy chiral catalyst papers, though, on that I think we can all agree.

Nope. I don't. No one goes into a program expecting the result to be 'lousy', but once they find it was, then I think there should be an effort to report it. A responsibility even (at least for government funded research). What we don't need are researchers repeating work that gives lousy results just because it wasn't reported.

I get your point. I agree that we don't need a 'lousy' paper that shows a good result in an extremely limited or simple model space. It should also show an effort to stretch the result to a more difficult model (attempt to anyway). Sort of a "this result encouraged us to try X, but sadly ......". IMO that kind of thing bears reporting.

Zz

Permalink to Comment

4. Hirsute on June 6, 2013 4:25 PM writes...

As my friend conviniently pointed out, it's also a Science research article, and not just report as some slackers do it

Permalink to Comment

5. Ouabag on June 6, 2013 5:51 PM writes...

I wonder if someone is doing half and half chemistry and biology to "dual catalysis"?

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6. Hirsute on June 6, 2013 7:29 PM writes...

@ Ouabag,

like this?
http://pubs.acs.org/doi/abs/10.1021/jo990956w

Permalink to Comment

7. Click-slacker on June 6, 2013 7:40 PM writes...

Obviously Science research articles require the perfect combination of not just one, but two known concepts. Luckily for Ouabag and myself, reports require only one.

Permalink to Comment

8. Click-slacker on June 6, 2013 7:40 PM writes...

Obviously Science research articles require the perfect combination of not just one, but two known concepts. Luckily for Ouabag and myself, reports require only one.

Permalink to Comment

9. Ouabag on June 7, 2013 1:57 AM writes...

No. More like relay between some wild-type enzyme and organic catalyst.

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10. No Clickity on June 7, 2013 10:01 AM writes...

Click-slacker, you have such a big ego, must be a very tall guy...

Permalink to Comment

11. Hardass Slavedriver on June 7, 2013 11:00 AM writes...

To all the whiny slackers in SoCal:
You have too much free time on your hands!
Go back to the hood!
DO IT...JUST DO IT NOW!!!

http://www.youtube.com/watch?v=u6ALySsPXt0

Permalink to Comment

12. ST on June 7, 2013 4:25 PM writes...

Just stay in europe

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13. John on June 17, 2013 7:57 PM writes...

Carreira group? I await the success of this chemistry in a different lab. I have had...mixed results reproducing reported ERs from this group.

Then again, dr in this case might raise the ee, as it is highly unlikely that you would get a mismatched-mismatched reaction giving the wrong enantiomer. Clever.

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