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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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May 13, 2013

Pyrrolidines, Not the Usual Way

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Posted by Derek

I wanted to mention a new reaction that's come out in a paper in Science. It's from the Betley lab at Harvard, and it's a new way to make densely substituted saturated nitrogen heterocycles (pyrrolidines, in particular).
You start from a four-carbon chain with an azide at one end, and you end up with a Boc-protected pyrrolidine, by direct activation/substitution of the CH bond at the other end of the chain. Longer chains give you mixtures of different ring sizes (4, 5, and 6), depending on where the catalyst feel like inserting the new bond. I'd like to see how many other functional groups this chemistry is compatible with (can you have another tertiary amine in there somewhere, or a hydroxy?) But we have a huge lack of carbon-hydrogen functionalization reactions in this business, and this is a welcome addition to a rather short list.

There was a paper last year from the Groves group at Princeton on fluorination of aliphatic CH bonds using a manganese porphyrin complex. These two papers are similar in my mind - they're modeling themselves on the CYP enzymes, using high-valent metals to accomplish things that normally we wouldn't think of being able to do easily. The more of this sort of thing, the better, as far as I'm concerned: new reactions will make us think of entirely new things

Comments (9) + TrackBacks (0) | Category: Chemical News


1. luysii on May 13, 2013 10:48 AM writes...

Yes, but look carefully at the catalyst (which isn't shown in Derek's diagram). It involves iron in a very sterically hindered environment -- an adamantane group hanging off either side of the backbone from which the iron is suspended.

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2. Rhenium on May 13, 2013 11:23 AM writes...

I was wondering where the metal was myself, other than in the mysterious "2".

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3. Biomimetic on May 13, 2013 12:16 PM writes...

Both iron and manganese based catalyst systems can performed CYP related reactions. Recent publications (Groves) showed also the possibility to perform chlorination, fluorination and other interesting modifications. We developed a process to quickly survey these chemistries at HepatoChem.

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4. *rxn on May 13, 2013 2:19 PM writes...

Sweet! I love seeing new chemistry like this. I definitely agree with you, the more of this kind of thing the better! Thanks for the post.

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5. David Formerly Known as a Chemist on May 13, 2013 2:20 PM writes...

Now there's but another way for medchemists to make target molecules that the process chemists and pilot plants won't touch. "You want me to make HOW many kilograms of an API that requires 10X kilograms of an azide intermediate? What exactly have you been smoking"??

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6. steve on May 13, 2013 3:57 PM writes...

reminds me of lead tetracetate radical cyclisations of alcohols to ethers I did in my PhD. It would be interesting to make a chiral catalyst to see if one could get some enantioselectivity, though undoubtedly that's been done at the moment.

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7. Please think on May 13, 2013 8:55 PM writes...

#6 Being a former chemist this may have eluded you but AZT (a marketed drug) is an azide; I suspect it is prepared on significantly greater than single digit kilogram-scales. Usually the organic azide is not inherently unsafe (temperatures of exothermic decomposition onsets can be determined using calorimetry) but using azide salts on scale poses the risk of producing HN3. Yes this reaction may not be ready to prepare metric tonnes but few reactions are when first discovered. The bar would be quite high it that was part of the criteria for publication.

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8. a. nonymaus on May 14, 2013 11:50 AM writes...

Re: 6
The product chirality is likely determined by the position of the C-H bond that the nitrene-like intermediate inserts into. I'm a bit leery of the radical-rebound mechanism given their results with the cyclopropyl-substituted substrate. So, all you have to do is make the desired chirality of starting material. This really reminds me of reactions of singlet carbenes.

The other route to substituted pyrrolidines that I've seen in the literature is from the Stahl group at UW-Madison. It is an aerobic oxidative amination of a tosylamino alkene to give an N-tosyl vinylpyrrolidine.

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9. DrFreddy on May 16, 2013 10:59 AM writes...

Pyrrolidines stink--this reaction does not!

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