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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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April 17, 2006

Reading Our Own Press Releases

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Posted by Derek

So, what's the problem if some of the yields in total synthesis papers are a bit. . .enhanced? If the reactions worked, why get worked up about it?

Well, aside from nagging thoughts of intellectual honesty, there's a practical implication. Even if no one ever tries most of these reactions again - and believe me, no one will - the problem with advertising our mighty chemical powers is that people who don't know any better will believe us.

You can start with other chemists. We've all heard stories about people who've tried to repeat reactions from the Famous Labs of one or another Famous Professors and been unable to get them to work. It's to the point that synthetic chemists with some experience automatically discount the yields that they see from some groups, because they know that they can't reproduce them. (See the comments to yesterday's post if you want some concrete examples). The ones who haven't heard, though, will continue to discover the nasty reality on their own, often wasting their time and effort in doing so.

But I think the serious trouble starts when we get outside of the field. I've worried for some time that synthetic organic chemistry has been in danger of making itself seem more powerful and efficient than it really is. This can be a noticeable problem in industry, where you deal with molecular biologists, toxicologists, and other people who have to take our word for things. And if what they hear about are mighty synthetic chemists banging out mighty molecules in mighty impressive yields, what kind of reception do we mortals get when we tell them that we're having trouble making their lead compounds in enough quantity?

We really don't want to make people think that we can make everything, you know, because we can't. Not in any real-world sense, we can't. Experienced synthetic chemists all know this, because we've all been humbled by comparatively simple molecules and supposedly easy reactions. These things are smarter and trickier than we are, and they'll remain so for a long time to come. It would go easier on us if people outside the field knew that we can't just magically deliver on whatever they'd like us to make. And who knows, perhaps if word got out that organic chemistry isn't a tapped-out all-tied-up field, we'd get some more good people to come help with it.

Comments (26) + TrackBacks (0) | Category: The Scientific Literature


1. secret milkshake on April 17, 2006 9:24 PM writes...

Even if the results are solid, the way things are usualy presented on meetings is beautiful, tidied-up. Spectacular transformation are achieved in great yield. If your boss has not done any synthetic chemistry for a while, by himself, in the lab, his perspective could get distorted from all these beautiful papers and lectures.

Wishful thinking is dangerous in any science. Once you start fooling yourself, fooling others becomes very easy.

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2. Ryan K. on April 17, 2006 9:37 PM writes...

I have recieved open criticism from my previous advisor for changing the methadology of some reaction, but not signifigantly increasing yields. This kind of treatment of course leads to you starting to fudge your yields a little. You find yourself usuing moral equivalency to figure out how much you can lie and still live with yourself, compared to what the payoff will be with your supervisor. You know, you say "I got a 92% yield, well, at least I confidantly feel that the reaction could yield 92%...".

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3. highlyReactive on April 17, 2006 10:22 PM writes...

But if equations give such a nice outlook on what should happen then why are reactions such a crap shoot? Is it that not all molecules get to see the ones that they need to react with or that the molecules decide not to mix because they're in a bad mood? ;)

Oh and why would you want to draw more *good* people into the field if pharma is laying off people left and right?

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4. secret milkshake on April 17, 2006 11:59 PM writes...

We are hiring.

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5. Ryan K. on April 18, 2006 12:18 AM writes...

Reactions are sometimes a crapshoot because we fail to recognize that what we do alot of the time is really alchemy. Chemistry is a science of understanding reactions, not necessarily engineering them to work everytime... that's the where the magic comes in. There really is a bit of magic in much of the work we do.

I can think of one particular reaction I tried 5 times in a row, using the same bottle of starting material, same conditions, etc. On the third try I got a ~60% yield of super clean product, as bright white crystals after recrystalization. Every other time I was completely unable to isolate any usable product from the reaction. There are so many possible variables... But then again, some reactions work perfect every single time you attempt them, even when using new reactants. Or sometimes a reaction will work perfectly when you start with old, dirty, and possibly contaminated starting material. But when you reattempt the reaction using fresh, sparkly white starting material it fails miserably. Now that's the magic of contaminants stabilizing and/or catalysing your reaction!

It has been found many times that reactions will only work using one reagent or solvent from one particular source or geolocation. A little bit of Ruthenium contamination in Na2CO3 that helps cocatalyse your palladium mediated coupling for instance. Without that particular salt sourced from the northern urals, the reaction doesn't work. Etc...

And I'm not even going to go into the art of growing crystals. For that, you sometimes really just need to have the midas touch.

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6. Ryan K. on April 18, 2006 12:21 AM writes...

Hire me!!! Besides, I have always gotten along really well with milkshakes!

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7. Thomas E. McEntee on April 18, 2006 6:18 AM writes...

Back in the stone age (1973-81) when I actually put my hands on glassware and developed manufacturing processes (2000-4000 gal) for what the younger folks call "small molecules", and oh by the way, was expected to be out in the plant to answer questions while my processes churned out profits, telling the plant manager that chemistry was "a science of understanding reactions, not necessarily engineering them to work everytime..." would have been met with scorn and a quick report to the General Manager that one young PhD chemist needed to be shipped somewhere else. If your reactions don't work every time, you've failed the understanding part...

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8. Harry on April 18, 2006 7:08 AM writes...

Actually one of the "simple" processes I've had the most trouble replicating is catalytic hydrogenation. I've rarely had one run anywhere as well as the literature indicates, and I usually end up using a different catalyst at a higher concentration and more (sometimes MUCH more) extreme conditions.

This is an area that seems to still have a huge element of "art" in it.

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9. MikeT on April 18, 2006 7:38 AM writes...

I am also available for work. What I really would like to do is find new natural products out in the world, or have others get them for me, find out if they are useful, and then try to make them. Then recieve a paycheck for this. Anybody? Or, did this end in the 70's?

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10. rhodium on April 18, 2006 7:55 AM writes...

This topic seems to have hit a nerve, especially looking at the last post and continuing here. Synthetic chemistry is not the only bastion of art in science. When we started doing some bacterial cloning many years ago I noticed that nothing ever worked the first time. Either I or my students would have to do a given kind of procedure (plasmid prep, ligation, etc.) several times, often with the same protocol, until it worked. Once it worked it essentially always worked. We thought we were not changing things, but obviously we were. Today, with so many kits, the problem is lessened, but still shows up. On another topic, no, I never heard of until yesterday. Rhodium got me tenure, so its my favorite square on the periodic table. Finally, can somebody start an Corey group blog? We don't want the oral traditions to die out as we sail off to that undiscovered country. Of course we might need NSA to do the site security due to posters' paranoia levels. Even today when I hear a door close I get the urge to jump out of my seat.

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11. Derek Lowe on April 18, 2006 8:03 AM writes...

Thomas McEntee's comment (#7) is a good example of the divide between discovery and process chemists that I was talking about the other day. He's right - engineering reactions so that they'll work every single time is a big part of the job description of a process chemist, particularly when you get to the scale he's talking about.

But Ryan K. is right from the standpoint of an early-stage discovery chemist. We don't have the time to work out why our reactions act so oddly, because there are too many other things to do. New analog made in 30% yield for some reason? Send it in and make the next one. We'll worry about the details if it makes it through the assays.

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12. Jonathan Gitlin on April 18, 2006 9:20 AM writes...

How do you chemist-types feel about advances such as those from Jay Keasling's group at UCB - bioengineering synthetic pathways from plants into yeast cells to produce small molecules in large numbers without getting chemists involved?

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13. Denni on April 18, 2006 9:32 AM writes...

I second rhodium's input--plenty of yinxes in (molecular) biology!

In one lab I know of they could not grow a particular microorganism described in a paper by a French group, no matter what they tried. Eventually, one of the researchers flew out there and discovered that the guys mixed their medium--with tap water.

The things grew perfectly in whatever was present in the local water.

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14. Demosthenes by day on April 18, 2006 9:51 AM writes...

When we were in grad school we had a bottle of aspirin packed in a mailing tube with the following label: Famous Chemist Pain Relievers, to be used when trying to recreate yields reported in the literature. (Packed under Argon)
Because I've grown older and somewhat wiser I just laugh at the 95% yields 50% of which is silica gel.

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15. Milo on April 18, 2006 10:55 AM writes...

Milkshake, could you email me? I have a question for you. There is a link on my blog with my address (just click my name, above :-)

Jonathan, I personally think that kind of technology is fantastic, especially for the removal of persistent chemical pollutants and synthesis of novel complex structures.

One of the things I have noticed whist postdocing in a group mainly made of biologists is that organic chemistry is in fact a mystery to a lot of people (at least here). When I give a talk, a lot of people struggle with the basics, like the difference between an amide and an ester (no joke!), I completely lose most of my group by the time I get to the mechanisms :-)

The idea that we may be more powerful and efficient than we really are is partly our own doing (yield inflation, pretty talks) and partly the doing of those who are not familliar with the field (simply by not understanding the synthetic process).

For example: I was recently approached by a cell biologist who wants to look at cellular localization of a particular substrate. She came up to me and says "Can you make a derivative of this substrate that is 1: cell permeable 2: fluorescent 3: stable to GST and esterase...". Turns out her cells were all grown and she needed it in 2-3 days.

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16. Paul Dietz on April 18, 2006 11:31 AM writes...

I suggest the following solution. Grant-giving agencies should devote some fraction of their budgets to independent confirmation of randomly selected results. If research results done under their grants cannot be reproduced, the researchers should be penalized, for example by denying them additional grants for some period of time.

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17. Mark on April 18, 2006 11:32 AM writes...

"we've all been humbled by comparatively simple molecules and supposedly easy reactions."


Show me an arrogant synthetic chemist and I will show you a chemist who either hasnt done anything new or hides behind falsified data.

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18. secret milkshake on April 18, 2006 11:34 AM writes...

well, natural products are much out of favor with pharma companies now. As a medicinal chemist I can see why - they are just too damn hard to elaborate and scale-up.

There was a saframycin project at Celera in San Francisco, that site just closed down. There is a small company in Boston, Microbia, but from what I understand they pulled out of many of their original natural product projects in favor of synthetics. There is spanish company PharmaMar that did etinoscidine few years back and some companies did discodermolide and staurosporins, beta lactam antibiotics are still going on, etc. But it in a minority. If you want to do interesting natural products, stay in academia.

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19. RET on April 18, 2006 1:30 PM writes...

As an academic currently running a medium-sized synthetic group I feel I can add a bit to the on-going discussion. First, inflated yields are a result of expectation placed on the coworkers. An advisor that expects a certain level with get that level whether it is scientifically sound or not. In contrast, an advisor that asks students for quality results and responds to a 50% yield with "What is happening to the rest of the material?" will stimulate thought towards improving the process but not deem it essential. Unfortunately, these same people review papers and reject interesting NEW chemistry simply based on moderate yields and selectivity.

I wish to comment also about the natural product discussion. While it is true that these compounds as potential pharmaceutical agents are now more likely to originate from academic labs or small, risk-taking, biotechs, this should not be viewed as a wise move. >60% of the current pharmacopea originated from natural product leads. Moreover, recent efforts from the pharmaceutical industry have not identified compounds with unique biological activity (22 new drug targets from 94-04). Natural products offer significantly greater chemical diversity and they have already been designed to be water soluable, cross membranes, and affect biological processes. Synthetic methods for their synthesis can provide significant quantities for preclinical studies (Novartis/discodermolide) and genetic engineering of their biosynthetic machinery will allow the large scale production in heterologous organisms.

I understand that running natural products groups is expensive and new chemical entities are slower to germinate than synthetic groups but in the long run the two complement each other beautifully.

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20. Anonymous on April 18, 2006 1:30 PM writes...

I'd gladly stir the milkshake for a job in big pharma

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21. Jonathan Gitlin on April 18, 2006 1:58 PM writes...

One of the things I have noticed whist postdocing in a group mainly made of biologists is that organic chemistry is in fact a mystery to a lot of people (at least here). When I give a talk, a lot of people struggle with the basics, like the difference between an amide and an ester (no joke!), I completely lose most of my group by the time I get to the mechanisms :-)

Heh, sounds like you're talking about me. Loved chemistry more than anything else in HS, then went to university to do Pharmacology as an undergrad and since then I've struggled to remember a tenth of my IB chemistry. The fact that we had to learn to call things alkanones and alkanals instead of ketones and aldehydes like the rest of the world didn't really help. Still, I envy the life of a chemist.

I was at Scripps for my first postdoc, and saw how much easier the chemists had things compared to us poor bioscientists. One year postdocs, jobs lined up by the Chem department, big shiny building etc... Plus chemists never have to spend six months waiting for mice to breed.

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22. Milo on April 18, 2006 3:18 PM writes...

"Plus chemists never have to spend six months waiting for mice to breed."

Yeah, but how many synthetic chemists can do good in vivo studies? It is nice when it is a two way street: The bio folks assay my products and give feedback and suggestions and I make interesting molecules for them. Most of the time we get along great.

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23. boiledonions on April 18, 2006 6:19 PM writes...

As a graduate student I was once confronted by my advisor as to why I could not reproduce the

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24. eugene on April 18, 2006 8:48 PM writes...

Jonathan, the technology you are talking about is really great and I've heard about it before. Only a little while ago it seemed unpractical, and now, there are a lot of people that are working in biosynthesis of select compounds (small molecules was only going to be a matter of time). However, this is still a lot more expensive and takes a lot more time than to generate a library of compounds by organic synthesis. If you sit down and think about your drug, and think that it will bind to the protein better if you take out a methyl group somewhere on the inside, then it's going to take a lot less time and money for the organic chemists to make it, then for the biologists to train a bacteria how to do it and isolate the product.

Ultimately, organic chemists are not there to make tons of a certain small molecule. That's more of the engineering side of things. And if yeast can do it better than an industrial reactor, then more power to the engineers.

Now, if you can change the plant pathway to knock out a carbonyl somewhere in the middle of your molecule when you just change the gene sequence after a few days of work, that would be something that would put a lot of synthetic chemists out of work.

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25. Chrispy on April 19, 2006 11:55 AM writes...

Doesn't everyone know about the Corey 1-2 inversion? That is, if you have a reaction that goes in 29% yield, the magic of the Corey 1-2 inversion makes it 92%...

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26. Anonymous on April 30, 2006 2:28 AM writes...

I really appreciate this and the previous post/comments. I'm doing a PhD in natural product synthesis with a very laid back supervisor. I really enjoy it and spend a lot of time in the lab, so much so that I'd like to post doc with one of those famous groups with huge publication lists however stories relating the bad aspects of these big groups are hard to come by.
The PI's seem to be able to treat people this way (ie. over-work or no respect) simply because they have a steady supply of wannabe stars applying for positions. If the next generation of scientists demanded more civility, I'm sure the big bosses would get the hint pretty quick.

I'd really like to hear more stories about people's experiences in big groups (both good and bad) if only to decide where I want my career to go in the next few years.

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