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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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January 3, 2014

Easy Aziridines

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Posted by Derek

Organic synthesis is, as many have put it, a victim of its own success. Synthetic chemists can, it's true, pretty much make whatever plausible structures you can draw on the board, or whatever product some tropical fungus or toxic sponge thinks is a good idea. But we can make those only if constraints on time and money are removed. "Give me enough postdocs and I will move the Earth".

Those aren't realistic conditions, though. There are many types of compounds, some of them quite simple, for which no good synthetic routes are known. Under infinite-postdoc conditions, many of these can be worked out for specific cases (step 43 of the total synthesis of shootmenowicene), but (and here's my industrial bias showing), a good synthetic route is one that works on a variety of substrates, with readily available reagents, in reliably useful yields, under non-strenuous conditions. We're missing a lot of those.

But it looks like one might have been crossed off the list. This paper in Science, from UT-Southwestern and Brigham Young, reports a new method to make aziridines, including NH ones, in one step under mild conditions. There are quite a few methods to make aziridines, but most of them are N-substituted, particularly N-Boc and N-tosyl. A direct reaction analogous to epoxidation to give you an NH aziridine is pretty rare, but this seems to be the answer. It's a rhodium-catalyzed route that has been applied to a range of olefins, and it looks pretty mild and pretty general.

This should simplify routes to a number of natural products with this motif, but it should also prompt some new chemistry as we get easier access to that functional group. Congratulations to the authors!

Comments (10) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anonymous on January 3, 2014 12:18 PM writes...

Give me enough grad students and a lab for me to place them, and I shall synthesize the earth

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2. cynical1 on January 3, 2014 12:19 PM writes...

Maybe someone should make Zafgen's Met-AP2 inhibitor that has the two epoxides in it but with two aziridines instead. Think that'll fly?

Actually, that's a pretty cool transformation because you can do a lot of chemistry with a 'naked' aziridine but I'll leave it out of my final analogs if you don't mind. Thanks for pointing this paper out. There's a mistake in Fig 2 under entry 18. I think it's supposed to be '72% of 10q' not '72% of 10p'. I was scratching my head when I was just looking at the figures at first. I also hope one of the major chemical suppliers starts selling the hydroxyl amine for less than $200/g. It's easy to make...........but who wants to.

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3. anon the II on January 3, 2014 12:49 PM writes...

Thanks for pointing out this paper. Nice follow-up work on a casual observation. It's a new arrow for the synthetic chemist's quiver.

Emolecules shows a source for the amine at around $30/g (http://www.chemcia.com/product_fl02.asp?id=69), in stock.

It will interesting to see what chemistry comes out of this work. I remember all the new useful things that came from simple boring diols once Sharpless showed how to easily make them chirally.

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4. stir_bar on January 3, 2014 1:01 PM writes...

The "Kurti" schemes drive me up the wall. Other than that, this is interesting chemistry.

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5. Justin Peukon on January 3, 2014 1:10 PM writes...

My contribution to New Year grumblings:
For sure, everything is possible. So, reviewers, please STOP to ask for ridiculous extra experiments, like 900 MHz 1H-NMR spectra, neutron single crystals diffraction, 0.000001 mK magnetic susceptibility data, and 200% yield reactions. Especially when the paper you review is about a diamagnetic amorphous sample of a naturally occurring oxide which has no H in its formula. Yeah, I'm kidding, but it's sometimes more or less the situation.

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6. anon the II on January 3, 2014 1:58 PM writes...

Interesting! In the acknowledgements, they thank Corvinus Chemicals, LLC for contributions of the aminating reagents. As it turns out Corvinus Chemicals, LLC is owned by Kurti and Falck.

Maybe, next time I write a paper, I'll thank myself for preparation of some of the intermediates.

Still, nice work.

Permalink to Comment

7. cynical1 on January 3, 2014 2:32 PM writes...

But to everyone else, according to their website, Corvinus Chemicials sells it for $200/g. I think if I were them, in academia, I'd lower the price to get more people to use the chemistry so they get more citations on their paper. Or is that a cynical thought?

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8. nekekami on January 3, 2014 3:05 PM writes...

@7:

No, if you want to be really cynical, this is more like it: Does Corvinus Chemicals LLC have their own facilities, or are they in fact using faculty labs to manufacture their products, or are they just contracting out to asia?

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9. Nick K on January 3, 2014 9:06 PM writes...

I don't have access to the full paper, so I'll ask the question: did they try using a chiral rhodium ligand to make enantiomerically-enriched aziridines? If not, this would be an obvious and valuable extension of the work.

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10. Anonymous on January 4, 2014 4:35 PM writes...

Synthetic chemists are not victims of their own success. They largely just dont take advantage of what they have made, or sadly are not taught how to think that way. They have produced amazingly powerful tools to make stuff. Its just that improvements are largely incremental and the real opportunities are to use those wonderful tools to make/discover functional molecules. For those who do that, the world is their oyster. Improvements are certainly welcome and needed, but just be content with a decreasing visibility on the Science stage. Interesting example: Organic chemistry textbooks are largely unchanged in 20 years (or more!) The same can't be said for other fields-biology certainly comes to mind. Those textbooks are almost rewritten every 5-10 years. Not to mention fields where there is barely enough to write a textbook. Science marches on...

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