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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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May 8, 2013

Total Synthesis in Print

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Posted by Derek

Over at the Baran group's "Open Flask" blog, there's a post on the number of total synthesis papers that show up in the Journal of the American Chemical Society. I'm reproducing one of the figures below, the percentage of JACS papers with the phrase "total synthesis" in their title.
You can see that the heights of the early 1980s have never been reached again, and that post-2000 there has been a marked drought. As the post notes, JACS seems to have begun publishing many more papers in total around that time (anyone notice this or know anything about it?), and it appears that they certainly didn't fill the new pages with total synthesis. 2013, though, already looks like an outlier, and it's only May.

My own feelings about total synthesis are a matter of record, and have been for some time, if anyone cares. So I'm not that surprised to see the trend in this chart, if trend it is.

But that said, it would be worth running the same analysis on a few other likely journal titles. Has the absolute number of total synthesis papers gone down? Or have they merely migrated (except for the really exceptional ones) to the lower-impact journals? Do fewer papers put the phrase "Total synthesis of. . ." in their titles as compared to years ago? Those are a few of the confounding variables I can think of, and there are probably more. But I think, overall, that the statement "JACS doesn't publish nearly as much total synthesis as it used to" seems to be absolutely correct. Is this a good thing, a bad thing, or some of each?

Comments (31) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


1. Henry's cat on May 8, 2013 10:23 AM writes...

Might it be the case that in the old days, papers to do with the total synthesis of a particular molecule were just that: a total synthesis? One target:one paper. Yet more recently, in order to squeeze out as many communications per target as possible we see more papers with 'studies towards the synthesis of the Eastern hemisphere' of natural product x; watch out for the Western hemisphere in six months' time.

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2. student on May 8, 2013 10:31 AM writes...

I think it's probably the case that JACS is still just as eager to publish total syntheses, but the funding is no longer there for the armies of grad students and postdocs that synthetic groups need to pump these papers out (this is a low publication/person field). How many groups are still able to fund the 30-50 student groups that used to be common even in the second-tier R1 synthetic mills a decade or two ago?

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3. Curious Wavefunction on May 8, 2013 10:43 AM writes...

It's interesting to note that even though the percentage of total synthesis papers has gone down, the "most read" and "most cited" lists in JACS still include a healthy sprinkling of total synthesis articles.

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4. KNP on May 8, 2013 10:48 AM writes...

Not sure if this is what you were asking about JACS publishing more papers around 2000, but Stang had a nice infographic about that spike in his recent C&En writeup (graphs towards bottom of article)

Not quite a direct comparison to ACCEPTED articles, but you can probably get a sense of it...

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5. Total on May 8, 2013 10:49 AM writes...

@2, spot on! If you are a medicinal chemist like me, then you are looking for those papers on the interface of chemistry and biology. So, I have total loss of interest in total synthesis. Once in a while you will see some interesting work to demonstrate the methodology developed for the total synthesis, which is OK. I still miss the kind of synthesis carried out by the likes of Larry Overman and others!

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6. Ex-tot syn on May 8, 2013 10:53 AM writes...

As someone who went through grad school in the great 00's, and published two syntheses (one accepted in JACS, one not), I definitely had the sense even then that reviewers were skeptical of even high quality total synthesis papers. 'What does making another random natural product add to the field' was the general impression I got. Whether that is true or not can be debated, but I think I visual inspection of JACS should tell you that the focus of the journal has shifted well away from organic synthesis of any kind. Probably this is an accurate reflection of where the field is going.

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7. Evans' Dog on May 8, 2013 11:03 AM writes...

the cabal of Nicolaou, Corey, Evans, Danishefsky were far more effective in gaining funding and influence for MERELY getting a TS done. these groups have significantly down sized (natural age-ing process). The current torch bearers baring the Baran group just don't pass muster in carrying the field to new heights.

Obviously - the squeeze in funding has a small role to play, but the lack of dynamic approach to complex molecules is the real issue. Creative and practical synthesis will still count and the current generation has a taller order to fill.

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8. Andre on May 8, 2013 11:24 AM writes...

This must be partly due to the increase in interest in different fields of chemistry. The timing seems to correspond to an increase in focus on biochemistry and materials.

A brief (yet completely unscientific) look at this week's JACS from 30 years ago highlights the dramatic changes in focus that have occurred. Ignoring total syntheses in particular, JACS of old seems much more synthetic focused (both organic and small molecule inorganic).

I'm actually surprised that total synthesis as a topic is still as prominent as it is. I would have suspected that it would have been exiled to field specific journals to a greater extent.

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9. See Arr Oh on May 8, 2013 11:47 AM writes...

@Andre - Hark, do I hear a call for "The Journal of Total Synthesis?" I'm sure we could put together a de facto Editorial Board just by grabbing commenters' names from this thread...

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10. Hap on May 8, 2013 12:44 PM writes...

7: Really? Palau'amine was pretty neat, and both Sarpong and have done pretty neat alkaloid work - it certainly beats a lot of the "horde of postdocs" syntheses of the 90's and the earlier "aldol your way to greatness" phase. (And of course almost none of these syntheses actually solved the problems that formed the purpose of the work). I'm not seeing the shortage of novel ideas - funding (for profs) and jobs, yes, but not ideas.

Total synthesis may be diminished, but there seem to be a lot of methodology papers anyway. I like total synthesis papers, but lots of people liked physical organic papers, too, and chemistry has shifted some from its pure exposition (if not its principles). Things change.

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11. Evan's Dog on May 8, 2013 12:54 PM writes...

Sarprong ?? did you just cook that up !

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12. bbooooya on May 8, 2013 1:14 PM writes...

Maybe the uptick is due to people finding more T's to cross and I's to dot?

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13. uknowwho on May 8, 2013 1:26 PM writes...

total synthesis of natural products has been dying for years now. very few reasons left to do it, save for the occasional compound with interesting activity. the cost/benefit is too high, although it is still a good way to train students in molecule making. although, there is hopefully better justification for a field than "good to train students".

trying to get "ee" is not much more appealing. both areas seem like they are still done because most academic organic chemists dont have higher ambitions, they can be done without risking much-(God forbid you learn something after your postdoc), and there is a 30-50 year old formula for each.

maybe not a huge surprise that most consider much of organic chemistry as becoming insignificant. sorry folks, the field is going to have to find better ways to justify itself, most effectively by asking bigger questions.

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14. Andre on May 8, 2013 1:34 PM writes...

@See Arr Oh: You're barking up the wrong tree if you want to start a JTS (although it may very well warranted)

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15. Hap on May 8, 2013 1:39 PM writes...

...except, in lots of cases, the ability to answer larger questions depends on the ability to make the correct tools that work under useful conditions (peptide ligation, for example) which is the bailiwick of organic chemistry. I would not be holding my breath waiting for biologists to develop those methods on their own - if it's going to be done, chemists will have to do it. It's possible that combinations of existing methods can achieve those ends, but probably not, in which cases, someone's going to have to find new reactions.

Organic chemistry may not be an end in itself anymore (because we seem to have given up on making anything new), but it isn't irrelevant. Asking big questions is good, but big questions generally require lots of little questions to be answered.

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16. uknowwho on May 8, 2013 1:49 PM writes...

hap: the whole field is asking small questions: 1. synthesis of compound we dont care about using old methods or worse yet old methods resold as new methods or 2. cat. enantioselective organo/metallo/microbe catalysis of some old reaction. wake up, ee is not a big problem. in 1990, sure, now no.

some people have got to be asking bold new questions, trying to define new fertile fields, yes, using organic chemistry. the balance of small (no) questions/big bold questions is way off, its like 99:1 or worse. on its current low ambition track, it is riding out into the sunset in terms of relevance.

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17. Am I Lloyd peptide on May 8, 2013 2:08 PM writes...

To me Tot syn basically looks like trying to find more ways to get to the Everest summit. Is it really an achievement if you take a roundabout route over crevasses and gullies just to prove that you have more stamina or that you spied a flower than others had not seen before?

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18. Chemjobber on May 8, 2013 2:11 PM writes...

10: It's "aldol your way to tenure" -- ftfy. And it worked!

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19. Hap on May 8, 2013 2:13 PM writes...

If organic chemistry is irrelevant, it's either because no one cares about the questions it answers (mostly true, though I would posit, wrongly so) or because there is a better way to answer the questions people do care about. Who is asking big questions, and are they actually answering any of them?

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20. uknowwho on May 8, 2013 2:27 PM writes...


No, it's becoming irrelevant because the practitioners don't actually know how to ask a big question. It's partly not their fault because they were trained by a system (most academic org synth) that has not pushed itself to evolve.

Let me make an analogy. If someone has devised pretty good nails and hammers, somebody has to go build something interesting with them, rather than everybody going around trying to shave a micron of steel off the nail to optimize it. You have a bunch of tool builders who dont know enough (or are not courageous enough) to use the tools to achieve something really spectacular. They love to build molecules and they are really good at it, but they dont know what to build. Sure, its worth some portion of the field (10% ish) optimizing reactions, but if that number continues to be 70-90%--big problems wrt/ funding and relevance.

If the "big questions" left in organic chemistry are ee and nat prod synthesis, it deserves to have a diminished role in Science.

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21. David Watts on May 8, 2013 2:48 PM writes...

Only a matter of time before someone superimposes this graph over the one of declining productivity in Pharma and cites lack of ts as the cause of the problem.

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22. Wavefunction on May 8, 2013 2:50 PM writes...

To be fair, the "aldol your way to tenure" phase is not unique to organic synthesis. "Microfluidics your way to tenure", "GWAS your way to tenure" and "String theorize your way to tenure" are more recent forms of the same disease. Very soon it's just going to be "Speak on the lecture circuit your way to tenure".

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23. darwinsdog on May 8, 2013 4:40 PM writes...

I expect that drop is not unique to JACS but that is does trend nicely with declining NSF and NIGMS grant funding. I'm somewhat romantic for the total synthesis days, ahh what a wonderful old boys club pissing contest we had, but realistic in that it was no longer delivering for the investment. But show me a new reaction to label a protein in cells and I will be just as thrilled as I ever was with a palytoxin synthesis.

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24. SteveM on May 8, 2013 6:08 PM writes...

Re:#13 uknowwho "the cost/benefit is too high"

As an aside, a Management Science prof I know convinced me to use benefit/cost instead.

Because you can't divide by zero.

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25. Greg Hlatky on May 8, 2013 6:32 PM writes...

1980-2012 non-patent publications with "Total Synth.." in title, Organic section of CAS

1980: 282
1981: 340
1982: 320
1983: 330
1984: 356
1985: 394
1986: 417
1987: 397
1988: 387
1989: 417
1990: 401
1991: 395
1992: 347
1993: 476
1994: 485
1995: 434
1996: 512
1997: 488
1998: 544
1999: 564
2000: 595
2001: 566
2002: 591
2003: 670
2004: 602
2005: 650
2006: 689
2007: 686
2008: 727
2009: 801
2010: 748
2011: 662
2012: 631

So there's life in the old nag yet.

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26. lcc on May 8, 2013 7:16 PM writes...

I see a lot lot papers "Total Synthesis of something using authors favorite reaction". Total Synthesis in less than ten steps, including protection/deprotection. I feel top journals trend is more convincing.

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27. lcc on May 8, 2013 7:17 PM writes...

I see a lot lot papers "Total Synthesis of something using authors favorite reaction". Total Synthesis in less than ten steps, including protection/deprotection. I feel top journals trend is more convincing.

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28. Mr. Gladstone on May 8, 2013 9:31 PM writes...

To the vast majority, total synthesis is a means to an end, a tool to make molecules that allow you to probe biological mechanisms - make drugs. The more efficiently you can make the correct molecules the faster and more precisely you get to the answer.

The best medicinal chemists are almost always the best synthesis chemists.

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29. Design Monkey on May 9, 2013 6:09 AM writes...

Mr. Gladstone on May 8, 2013 9:31 PM writes...

To the vast majority, total synthesis is a means to an end, a tool to make molecules that allow you to probe biological mechanisms - make drugs.


It should be, but it isn't. And definitely isn't so for vast majority of academic total synthesis crowd.
For them it's tool to get grant money, to crawl the academic career ladder, and stuff. Making drugs just doesn't enter the equation there.

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30. alig on May 9, 2013 7:03 AM writes...

Off topic, Derek did you see this:

The amount of money Americans spend on prescription drugs fell for the first time in 55 years, according to a report from the IMS Institute of Healthcare Informatic.

The expiration of patents on widley used drugs such drugs such as Lipitor and Plaviix helped send overall U.S. spending on medicines down 1 percent to $325.8 billion in 2012, the group said. Adjusting for population, per capita spending fell 3.5 percent to $898.

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31. Secondaire on May 10, 2013 10:09 PM writes...

@#28 "The best medicinal chemists are almost always the best synthesis chemists."

And vice-versa.

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