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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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August 2, 2013

Ingenol: A Walk In The Park

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Posted by Derek

The Baran group at Scripps has a whopper of a total synthesis out in Science. They have a route to the natural product ingenol, which is isolated from a Euphorbia species, a genus that produces a lot of funky diterpenoids. A synthetic ester of the compound as recently been approved to treat actinic keratosis, a precancerous skin condition brought on by exposure to sunlight.

The synthesis is 14 steps long, but that certainly doesn't qualify it for the "whopper" designation that I used. There are far, far longer total syntheses in the literature, but as organic chemists are well aware, a longer synthesis is not a better one. The idea is to make a compound as quickly and elegantly as possible, and for a compound like ingenol, 14 steps is pretty darn quick.

I'll forgo the opportunity for chem-geekery on the details of the synthesis itself (here's a write-up at Chemistry World). it is, of course, a very nice approach to the compound, starting from the readily available natural product (+) 3-carene, which is a major fraction of turpentine. There's a pinacol rearrangement as a key step, and from this post at the Baran group blog, you can see that it was a beast. Most of 2012 seems to have been spent on that one reaction, and that's just what high-level total synthesis is like: you have to be prepared to spend months and months beating on reactions in every tiny, picky variation that you can imagine might help.

Let me speak metaphorically, for those outside the field or who have never had the experience. Total synthesis of a complex natural product is like. . .it's like assembling a huge balloon sculpture, all twists and turns, knots and bulges, only half of the balloons are rubber and half of them are made of blown glass. And you can't just reach in and grab the thing, either, and they don't give you any pliers or glue. What you get is a huge pile of miscellaneous stuff - bamboo poles, cricket bats, spiral-wound copper tubing, balsa-wood dowels, and several barrels of even more mixed-up junk: croquet balls, doughnuts, wadded-up aluminum foil, wobbly Frisbees, and so on.

The balloon sculpture is your molecule. The piles of junk are the available chemical methods you use to assemble it. Gradually, you work out that if you brace this part over here in a cradle of used fence posts, held together with turkey twine, you can poke this part over here into it in a way that makes it stick if you just use that right-angled metal doohicky to hold it from the right while you hit the top end of it with a thrown tennis ball at the right angle. Step by step, this is how you proceed. Some of the steps are pretty obvious, and work more or less the way you pictured them, using things that are on top of one of the junk piles. Others require you to rummage through the whole damn collection, whittling parts down and tying stuff together to assemble some tool that you don't have, maybe something that no one has ever made at all.

What I like most about this new synthesis is that it's done on a real scale. LEO Pharmaceuticals is the company that sells the ingenol gel, and they're interested in seeing if there's something better. That post from Baran's group shows people holding flasks with grams of material in them. Mind you, that's what you need to get all these reactions figured out; I can only imagine how much material they must have burned off trying to get some of these steps optimized. But now that it's worked out, real quantities of analogs can be produced. Everyone who does total synthesis talks about making analogs for testing, but the follow-through is sometimes lacking. This one looks like it'll be more robust. Congratulations to everyone involved - with any luck, you'll never have to do something like this again, unless it's by choice!

Update: here's more from Carmen Drahl at C&E News.

Comments (33) + TrackBacks (0) | Category: Chemical News | Natural Products


1. NoDrugsNoJobs on August 2, 2013 8:49 AM writes...

I love the metaphor Derek, never quite heard or thought of it that way!

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2. Ronathan Richardson on August 2, 2013 9:27 AM writes...

Is the idea that ingenol covalently binds PKC and activates it? This PKC-activating mechanism (supposedly by mimicking diacylglycerol) that seems to be shared by phorbol, bryostatin, and englerin is pretty amazing.

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3. Curious Wavefunction on August 2, 2013 9:28 AM writes...

"The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men" - R. B. Woodward.

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5. pete on August 2, 2013 9:48 AM writes...

hi Derek - that's "Euphorbia"
(I did a mental double-take on: "Good Phobia" )

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6. Salsa Picato on August 2, 2013 10:42 AM writes...

Anybody wants to start taking a bet what's the next minotaur that the Baran lab will slay?

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7. a on August 2, 2013 10:56 AM writes...

Tour de force.

I approve of pictures of the exptl procedures.....but:

In the supporting information page SI-10, is that a giant plastic syringe used to transfer >20ml (probably closer to 50 ml) of the aldehyde intermediate? Why yes, yes it is! Nothing could go wrong there......

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8. Nick K on August 2, 2013 11:30 AM writes...

A wonderful achievement. Heartwarming to see total synthesis actually being used to make gram quantities of useful natural products.

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9. SupplementReader on August 2, 2013 12:33 PM writes...

Very nice synthesis.

@8 Final step = " yield ingenol (SI-15, 8.1 mg, 76%) as a colorlessfilm."

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10. samadamsthedog on August 2, 2013 1:01 PM writes...

Ingenol: Despite its name, not for the ingénue.

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11. daen on August 2, 2013 1:28 PM writes...

This is personally interesting to me, as both an ex-employer (LEO Pharma) and an ex-colleague from another company (Jakob Felding) are represented here. Pretty neat stuff!

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12. Pedantic Speaker on August 2, 2013 2:00 PM writes...

It is even worse than that, Derek: The only tools you are allowed to use are other balloon sculptures.

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13. Carmen on August 2, 2013 2:33 PM writes...

Work like this, year in and year out, is going to have to raise the bar. I'd be ashamed to tell you fine folks how much abyssomicin C I actually made during my graduate career.

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14. Biology on August 2, 2013 6:13 PM writes...

In this game, Kishi is the real god among lesser gods.

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15. Anonymous on August 2, 2013 7:18 PM writes...

@6 Total synthesis of Taxol in 15 steps.

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16. Kayce on August 2, 2013 10:23 PM writes...

@7: It´s a THF solution of an aldehyde, not tert-BuLi and the addition rate can be controlled much better than using e.g. a canula to transfer the solution.

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17. CMCguy on August 3, 2013 12:42 AM writes...

#15 Unless extremely simple, elegant and scalable a 15 step total synthesis of Taxol might only have academic value as I believe the supply from natural isolation or semi-synthetic routes is fairly well established commercially and generally adequate to meet demand that includes a few related analogs on the market or in development.

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18. Mr Self Destruct on August 3, 2013 10:44 AM writes...

Ok this is a slight aside, and not meant to detract from the nice synthesis but... On the linked Baran group blog page, there is a picture of a student kicking the fume hood, sash wide open, and with no safety goggles on. I recognize the photo is probably meant to be humorous, but given the widely-publicized academic lab safety events of recent years, this seems to support the notion that little has changed in most labs. Honestly, it's a bit atrocious.

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19. Mr. Reconstruct on August 3, 2013 1:31 PM writes...

@18 Well it appears obvious that this was done immediately prior to taking the photo since he is still wearing a coat and a glove. As someone that works near that lab, the whole building is so crazy about safety they nearly wear gloves to piss.

Dude, seriously, get a life.

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20. Anonymous on August 3, 2013 4:21 PM writes...

Wonder as to,

Where do they get the (+) 3-carene for $ 10/mol?
Does the total # of steps of synthesis take in to account the prep for allenyl aldehyde?

Just curious about those couple of things; It is nice synthesis and we always admire Baran's work.

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21. Anonymous on August 3, 2013 7:14 PM writes...

The one aspect I really like about Derek's blog (unlike other blogs) is that it's not full of self-aggrandizing gibberish

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22. Mr Self Destruct on August 4, 2013 3:55 AM writes...

@19 "Dude," I'm not going to apologize for taking safety seriously. If/When you leave your ivory tower, assuming you are able to secure a job, you'll find that industrial (pharma) labs are not so non-chalant about these things, in jest or otherwise. And there are a lot of very good reasons for this.

I, too, was cavalier as a synthetic chemistry grad student, but having seen enough accidents happen over the years, especially in scale-up settings, in retrospect I shudder at some of what I saw or did while in school. You also come to truly appreciate that your peers and/or employees should go home each day in the same condition they arrived in the morning. Setting proper examples is one of the many components to making that happen.

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23. Anonymous on August 4, 2013 7:52 PM writes...

@Mr Self Destruct: I understand your safety concerns but let me assure you that the safety standards in the Baran lab are very high and people take lab safety very seriously. That also means that you won´t see a person in front of a hood without wearing safety glasses, a lab coat and gloves. The picture is indeed meant to be humorous and the postdoc in question was neither actually kicking the fume hood nor was a reaction running in that hood at the time the picture was taken.

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24. El Gorrion on August 5, 2013 2:32 AM writes...

Hats off to the Baran group for this work. I was especially pleased to see photos in the SI for reaction set ups and colour changes - an excellent way to help reproduce this work.

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25. Anonymous on August 5, 2013 4:42 AM writes...

To the members and former members of the Baran lab, please keep up the good work and don't get irritated by those who don't get the humor of that picture in the post, which was obviously showing the frustration the author tried to convey. I found it funny to watch. If all the safety rules are meticulously met in your lab, then think of Mr. Self Destruct's comment as a reminder, because after all, he did spend his time reading and writing about your post. You can never be too cautious when it comes to safety, especially since I only want to hear good news about your lab. Congratulations!

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26. Mr Self Destruct on August 5, 2013 6:21 AM writes...

@23 & 24: thanks for the more reassuring responses, glad to hear it. Safety awareness is another good thing for the Baran students to take away from their time there then, it seems.

Although TR (24), I'm still a bit disappointed in what I'm hearing in the new releases... but glad to see you back on stage anyway.

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27. Radioalchemist on August 5, 2013 1:51 PM writes...

Radiochemical synthesis: Imagine a structure similar to the one above except that one of the blown-glass balloons contains a mote of radiative fire which flickers and bounces off the walls of its prison threatening to escape at any moment. If it does, it shatters the glass, radically changing the balloon structure it occupies, collapsing the whole into something altogether different and sending a zinging fireball off into space ricocheting off and collapsing any other balloon structures it comes into contact with. The trick is to build the original structure in a completely different way to the usual, including the spark whilst at the same time reducing the chance of decomposition and minimising wastage of the valuable spark itself.

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28. Anonymous on August 5, 2013 4:48 PM writes...

@Mr Self Destruct. You drive me crazy by acting like a gerk

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29. Anonymous on August 5, 2013 4:48 PM writes...

@Mr Self Destruct. You drive me crazy by acting like a jerk

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30. Anonymous on August 6, 2013 12:36 AM writes...

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31. anchor on August 6, 2013 4:57 AM writes...

@20 I am told that in India they are sold as essential oil for perfumery industries in tons! My search also revealed that 3-carene were utilized as stating material for chrysanthemic acid and also for L-menthol! So, it is cheaply available chiral pool.

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32. Curt F. on August 6, 2013 2:56 PM writes...

Mr Self Destruct: which is more important in your eyes -- safety, or the appearance of safety?

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33. syeda on November 4, 2013 3:05 AM writes...

Excuse me, but I must say that your reply to the doctor's blog is just ignorant. It's not an opinion that he's asking for your "agreement" on. Clearly, you just cannot grasp that you have complete control over psoriasis with your FOOD CHOICES. It is NOT a skin disease. He has been kind enough to set up a blog to help people. Until the "medical" establishment and people who like to be "patients" start thinking on their own, instead of blindly accepting the BS that is spoon-fed to us by Big Pharm and the doctors they personally train in American med schools, you will continue to be sick. Just remember, it is YOUR CHOICE to eat all the processed foods, drug-laden meats, hormone-laden dairy, and MSG (there are 200 names for it, and it's loaded in every fast food -and high end-restaurant in America)that you like. You allow yourself to be a pawn in their chess game. WAKE UP! Psoriasis is not a skin disorder

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