Miles Monroe and Synthesis Bashing — RVW #7

September 10th, 2007

Without further ado, here is Retread’s latest Rip Van Winkle installment, in which Rip feels much like Miles Monroe. My apologies for not posting it earlier; I’ve been occupied with other things. In fact, the apparent hectic state from which Retread was emerging when he wrote this post strikes me as similar to how I feel in coming back to this blog after not even checking it for so long: a little weird. — Paul

Sleeper is one of the great Woody Allen movies from the 70s. Woody plays Miles Monroe, the owner of (what else?) a health food store who through some medical mishap is frozen in nitrogen and is awakened 200 years later. He finds that scientific research has shown that cigarettes and fats are good for you. A McDonald’s restaurant is shown with a sign “Over 795 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 Served”.

Rip returned from the 100-year birthday blowout and band camp and began attacking a giant pile of accumulated unread journals. In the 9 August Nature (p. 630 – 631) he was amazed to read criticism of a 64-step, 22-year synthesis of an exquisitely complex molecule (azadirachtin) — a molecule for which it is easier to count the number of optically inactive carbons than the optically active ones. Back in the 60s, we were all impressed with how Woodward got the five asymmetric centers in one of the six-membered rings of reserpine (which was in use as an antihypertensive at the time, and whose fairly common side effect of depression was one of the clues leading to the amine theory of affect). Rip was surprised to find that the criticism was not that the synthesis was incorrect, but that the project shouldn’t have been done at all. Apparently, a significant body of organic chemists think this way.

Political correctness has left us with few groups that are safe to disparage. With apologies to one of them (Christians) I’ve got to ask, “What would Woodward do?”

Rip’s father went into the hospital shortly after his 100th, and is getting out 1 Sep, so it may be a while before he can respond to what this post brings forth.

Retread

Previous Comments

  1. Wavefunction Says:
    September 10th, 2007 at 9:42 am I think the whole debate about totsyn is getting tiring and jaded. Tot syns will continue to do totsyn, materials chems and comp chems and chem biols will continue to pursue their work with dedication and fervor. Science as a whole will always benefit. That will always be good.
  2. excimer Says:
    September 10th, 2007 at 10:14 am Synthesis is a game. It’s like chess. Not knowing how to play it will not really impact your life. Learning how to play can be fun. Learning how to play well takes years of dedication, frustuation and losing. In certain instances (Seventh Seal-style), learning how to play well will be extremely beneficial. Knowing how to play well can open new doors for you. Mastering it takes decades of work playing the game, but in the end, all you know how to do is play the game. Those who play before you now will live in your shadow, but in the end, all you know how to do is play the game.Derek Lowe responded to the Nature article’s picking and choosing of quotes in his blog. Ley took 22 years to make the damn thing because he was working on new ideas and reagents as a result of working on azadirachtin- and doing very admirable work in the process. (I just realized I inadvertently stole Derek’s chess analogy. My bad.)
  3. Derek Lowe Says:
    September 10th, 2007 at 11:17 am No problem – my analogies are public domain. One way to put it is to say that although Steve Ley’s total synthesis work is very good total synthesis indeed, I find it the least interesting and useful of his activities.No doubt this is partly the effect of nearly 20 years in the drug industry, but I pretty much had had my fill of the field by the time I finished grad school. As I put it as the time, “The world does not need another synthesis of this molecule. But I do.”
  4. Anonymous Says:
    September 11th, 2007 at 12:09 pm Is it (comparing total synthesis to chess) not Prof. KCN’s analogy that you both have stolen? If the total synthesis is chess-then what are the under grads, grads and postdocs who do it?Ley is undoubtedly a good player. Does it have many palyers unlike chess?
  5. Wavefunction Says:
    September 11th, 2007 at 1:03 pm Most of them are sacrificial pawns…but beware! One of them can turn into a rook or queen.
  6. Anonymous Says:
    September 11th, 2007 at 8:15 pm Wavefunction:You said it right. The play is at the expense of those people who do the required work- but they are used like pawns and the fame goes to the player. If and if there is any rook (/crook) or queen emerges, by mistake, again the show goes on and on! Paul Wender is absolutely right in suggesting that it is time that the TS folks do a meaningful, useful some bio related and relevant work than basking in the glory of making a target molecule by 100+steps total synthesis + investing the lives of 100 people in it. There can be a better way for sure for training the future chemists.
  7. Willyoubemine Says:
    September 12th, 2007 at 9:28 am I agree that total synthesis peeps need to quit the simple diterpenoid and simple alkaloid game for more important and meaningful synthetic challenges. But, I also think that it is some of the best training an organic chemist can get. I have done med chem, total synthesis, and some methodology development, and by far (not even in the same ballpark), the total synth work was more challenging and more educational.
  8. W Says:
    September 12th, 2007 at 7:18 pm Paul, you really sound like a founder of New American Chemistry.
  9. Cat Herder Says:
    September 12th, 2007 at 7:32 pm Willyoubemine,Out of curiosity. What sorts of targets would constitute meaningful synthetic challenges?
  10. W Says:
    September 12th, 2007 at 8:13 pm For example, try to make a superconductor at room temperature. But since this is so difficult and may lead to nothing, better found a family.
  11. W Says:
    September 12th, 2007 at 8:22 pm i meant, in a very concrete allusion, do no try to solve the origin of life
  12. Willyoubemine Says:
    September 13th, 2007 at 12:07 pm well, that is a great question. One that is clearly a subject of contention among TS’ists and non-TSists alike.Those targets with unprecedented molecular architecture, (i.e.) the ladder polyethers in the early 90’s or imidazole alkaloids like agellefarine and palau’amine, more recently. The Stephacidin nad related are interesting too. Those targets where true innovation and discovery is necessary to complete their synthesis, those are the meaningful synthetic challenges.

    Just my 5 sheckels.

  13. Cat Herder Says:
    September 13th, 2007 at 7:05 pm Willyoubemine,I tend to agree with you, I was just curious where you stand on the issue. I make exception for routes getting to molecules with *actual* interesting bioactivity if they cannot be isolated in sufficient quantities for study. That is, unless synthesis is also not going to yield enough to use for further study.

    I would submit that certain diterpenoid and alkaloid structure are still “challenging” under our accepted definition. The real key is being creative and daring in the planned synthesis. At this point almost all structures can be made somehow, its just whether we can do it in an elegant and efficient way.

    Are you currently a “TS’ist”?

  14. Willyoubemine Says:
    September 13th, 2007 at 7:14 pm I am currently a TS’ist. And I agree with some alkaloids and diterpenoids too…As well as including classics like Strychnine, Quinine, Morphine etc where newer methodologies or approaches can be truly nice to longstanding molecules.you a TSist?
  15. Retread Says:
    September 14th, 2007 at 10:58 am The Nature article kicked up a lot of commentary, a lot of which appeared on The Wall, interestingly enough starting about the time I sent post #7 in to Paul (30 August) so I’ll respond to the stuff in the Wall in this postSome of the correspondents (Eugene # 178) imply that some of the anger against total synthesis is because funding is finite and TS is getting too much, depriving worthier efforts in chemistry. Joel #217 says this more explicitly “We ascribe intrinsic value to the different disciplines because there are finite resources to pursue them. People are not arguing for the end of total synthesis, just a lessening of the emphasis in terms of funds and manpower”. Sort of like Smolen in “The Trouble with Physics” speaking of the domination of the string theorists.

    This is a battle that is fought in all scientific fields (look at the abandoned supercollider in high energy physics, the cancer genome atlas — critical letters can be found on this [ Science vol. 315 pp. 762 – 764 ‘07 ], etc. etc.). I have no way of knowing if this is true of organic chemistry or not, but as a reader of Science and Nature for the past 40 years or so, there has NEVER been a time where funding has thought to be adequate, where dire imprecations about the future of science (American English, you name it) due to inadequate funding were not made. Meanwhile the scientific enterprise has lept from strength to strength.

    Eugene also says (#208) “Of course another benefit of total synthesis is being pushed to your physical and mental limits by working like an indentured servant for four years.” This sounds like the internship. The time to learn that you can stay up all night and the next day taking care of a critically ill patient, is NOT when you are on your own in solo practice, but early in your training, so that when you are by yourself doing the same thing, you don’t have to wonder if you can do such a thing.

    TheEdge (#214) says something I think is quite important and which I’ll come back to in a future post “I think that most totsyn chemists undertake their projects for two reasons: to test their understanding of chemical reactivity, — “. Willyoubemine #220 — says the same thing, in greater detail and perhaps more eloquently.

    I’ve read no total synthesis papers since the 60s, so I don’t know if what he says “Total synthesis should be the chemistry equivalent of taking an in vitro study and running it in vivo, but our papers are rarely written like that, and people get the impression that we’re doing it to prove how macho we are.” is true. Certainly mathematical papers are written like that — all the false steps aren’t mentioned, and how the idea of the proof was arrived at is never mentioned. It started with Euclid and was reinforced by Gauss.

    Well this post is long enough. I’ll comment on the actual commonest on post #7 later. In the meantime two questions.

    #1 — is there a funding crunch in chemistry so that good nonTS work isn’t being funded?

    #2 — when (since the Woodward 60s) did the criticism of TS begin? No one would have thought of it back then.

    Retread

  16. W Says:
    September 14th, 2007 at 2:01 pm well, Mr. Willyoube, what we are trying to teach is “emotional intelligence”. If you don’t have it, your problem. No TS1 or any other gene, but just normal human sentiment.
  17. Cat Herder Says:
    September 14th, 2007 at 7:31 pm Willyoubemine,I’m trying to be a TSist but the gods are conspiring against me. Joining a TS group is proving more difficult than expected.
  18. Svejk Says:
    September 16th, 2007 at 1:05 pm In response to Retread’s Question #1:Having participated in some of the relevant funding deliberations, my impression is that
    a) the funding pie is small,
    b) the Total Synthesis field reliably gets carved out a healthy slice and
    c) there is a substantial amount of other solid research that is not getting funded.

    Why is this? As a community, we seek to enable the work of the most talented and dedicated chemists around. We are also highly (unduly?) attentive to the judgement of a handful of luminaries at the top institutions, who avidly champion the efforts of the up-and-coming Total Synthesis jocks. And the luminaries certainly have a strong case. Many of the most brilliant and hard-working younger chemists have, in turn, devoted themselves to furthering Total Synthesis. It is only when (if ever) Total Synthesis fails to provide intellectual rewards that the community will lack a cogent case for continued strong funding — it’s where a lot of the brilliant minds want to be engaged.

    So, is this good or bad for our discipline? It beats me — I’m not one of the brilliant minds who can answer that question.

  19. Great Molecular Crapshoot Says:
    September 16th, 2007 at 3:23 pm When discussing total synthesis one needs to separate path to target from choice of target. Synthesis of a natural product does not require molecular design and it seems that targets are often selected on the basis of synthetic difficulty. The discipline becomes like a sport (more mountainering than chess but the same egos) whose practitioners set themselves increasingly difficult challenges (in winter without oxygen or Sherpas…) to prove that they’re better than their peers. I believe that total synthesis as a discipline needs to re-invent itself by finding ways to devise unnatural products that are worthy of the synthetic arsenal that they can bring to bear
  20. W Says:
    September 16th, 2007 at 4:42 pm Now it’s getting thin here. Getting a first author seems to be more difficult than we all expected.
  21. TheEdge Says:
    September 16th, 2007 at 7:35 pm FWIW, I don’t think I’ve ever been described as eloquent or even coherent, Retread.
    I can’t speak to #1, but I think I can shed some light on #2. When Woodward entered the field of TS, we really couldn’t design syntheses of complex molecules. We’ve learned a lot about the design and reactivity of complex systems since then, culminating in syntheses of Palytoxin and Brevetoxin in the 90’s, proving that if you threw enough bodies at molecule, you could make anything. A lot of chemists took those syntheses as evidence that TS is a solved problem, and that it was time to move on to other pursuits. These chemists tend to assume that TS is there to “make things” and tend to ignore other aspects of the field, pursuits like “making things efficiently and elegantly” or “making useful things”.
  22. Darksyde Says:
    September 18th, 2007 at 6:08 am good nonTS work? Does such a thing exist anymore?Outside of hard-core biochemistry, inorganic/organometallic, and enzymology (which has always had funding crunches)… I remember a time when flipping through an article of JACS meant wading through about 20 communications of sketchy groups in a far-east second-world country making some sort of new nanotube or nanopillar or fucking nanostar by switching from cadmium to iron to suckmycoxium. And even in organometallic, these days, do we really want to hear how some unexplored inner transition metal can catalyze michael additions to 60% yield with 5% catalyst loading?

    Even fields like biophysics, especially structure, is beginning to engender a culture similar to TS, with the same notion of “we understand everything in theory now let’s just try everything we know/try elegant schemes to push for our end product”. And there are even the J. J. LaClair-like incidents in structure — like Geoffrey Chang.

    I think what we need to do is to all get together and admit to ourselves that Total Synthesis is not a science. It’s somewhere between art and engineering. And that’s fine. And we should still fund it. And we should still house it in the chemistry department. There’s still lots and lots of things we can learn indirectly from total synthesis, from methodology to biology to sociology, not to mention the PhD-level training (certainly higher than MA, at any rate) that the pursuit affords (for those who wish to continue in industry).

  23. Willyoubemine Says:
    September 18th, 2007 at 9:47 am TS not a science? As a field? Thats silly. There are examples of TS work which is closer in nature to an engineering endeavor. But, the major achievements are still science. Baran’s Chartelline, Myers Kedarcidin work, Sorensens Guanacastepene, Jamison’s ladder polyether work, and other less recent examples abound where discoveries and achievements are made through total synthesis.While i agree that a 2006 Org Lett total synthesis of Aspidospermine (for example) which is no shorter or more efficient than those already accomplished is closer to engineering than science, if, as you say Darksyde, TS is an engineering, than we as engineers are awful, terrible engineers.
  24. Willyoubemine Says:
    September 18th, 2007 at 9:48 am p.s. i dont think we are awful, terrible engineers.
  25. Anonymous Says:
    September 18th, 2007 at 4:17 pm Svejk Says:
    You mentioned that the Total Synthesis field reliably gets carved out a healthy slice of the funding pie which is small, and hence the other solid research doesn’t get funded.
    I was wondering if it would sell if one ties up the drug discovery kind of terms (the actual research that one wants to pursue) to the total synthesis of the fancy molecule ( since any body can come up with a synthesis plan to the fancy molecule) and do the research i.e survive in tight funding. There will be other factors that would decide the chances of funding but do you think it is a better shot to survive in TS dominated era. They neither do meaningful research nor allow others to do. Let us hear what others have to share on the funding crisis which is partly due to the so-called TS era.
  26. W Says:
    September 18th, 2007 at 5:15 pm I believe I ran across Bengu today, on the University of Heidelberg campus, close to the ZMBH. She appeared quite petite, long brown hair, looked similar to her photo on the ZMBH website, spoke English, but I did not dare to talk or to reveal my true identity to her. Too embarassing, wouldn’t you think so ?
  27. w Says:
    September 18th, 2007 at 7:53 pm Svejk ? no, just reality, without Harvard, exaggerated, I mean
  28. W Says:
    September 18th, 2007 at 7:55 pm Paul, you need to adapt your spam filter, you cannot publish anyting
  29. Tot. Syn. Says:
    September 18th, 2007 at 8:04 pm Surprise! I felt the need to comment here. Actually, I’m not going to step in and defend the entire field. There’s a lot of crap out there. I read pretty much every total synthesis in the major journals, but I only blog what I think is worth reading. And sometimes the papers are worth reading for “the wrong reasons”.The worst papers are those that: A) shoe-horn in the group’s methodology into a synthesis that ends out way too steppy. This is my take on synthetic inelegance. Or B): Are perfectly great – nice strategy, appropriate reactions and great results – but are effectively the latest in a long line of similar papers from the group.

    Aza-D is neither of these. The final synthesis needed to be done, but the project was all about the methodology created along the way. It’s a bit like say that half the fun in a holiday (vacation if you insist) is getting there. If one looks at the publications generated from the synthesis, not only are there lots, but they go into interesting places, like Org. Proc. Res. Dev. That’s a *good thing*.

    The other comment I’ll make harks back to comment 18 from Svejk. True, TS takes up quite a chunk of funding. But (at least in the UK) quite a chunk comes from pharma industry. And they like ‘TSists’ because if you can make a natural product, you can make a drug candidate (if you can dodge spanners, you can dodge balls…). And for the most part, total synthesis groups also work on methodology, so each feeds into each other…

  30. Kyle Finchsigmate Says:
    September 19th, 2007 at 6:53 pm You know, it was after the San Fransisco ACS that Dylan stopped blogging. And it appears as though the ACS has killed another blogger.BOYCOTT THE ACS FOR ITS WANTON DESTRUCTION OF BLOGS!
  31. Paul Says:
    September 19th, 2007 at 9:12 pm I’m a adopting a new posting schedule based on the greatest chemistry blog of all-time, “The Culture of Chemistry”.
  32. Ψ*Ψ Says:
    September 19th, 2007 at 9:54 pm hah! if i did that, no one would read cbc at all!
  33. excimer Says:
    September 20th, 2007 at 12:56 am yeah, cause, you know, noone else writes for cbc. Nope.…
  34. Ψ*Ψ Says:
    September 20th, 2007 at 9:52 am Dude, I meant if BOTH of us stopped posting. (Or just if you stopped posting. I’m convinced no one is there for my rambling.)
  35. joel Says:
    September 21st, 2007 at 10:48 am #15: Retread,Smolen presents some of those contepts, but my post was mostly inspired by something John Platt wrote 1960’s called “Strong Inference: Certain systematic methods of scientific thinking may produce much more rapid progress than others” [Science 16 October 1964 146: 347-353]

    This essay has given me lots to think about over the years, many humbling thoughts. And, to my own regret, i even stole a phrase from him.

  36. W Says:
    September 21st, 2007 at 3:08 pm Impossible. Everything that Paul writes here is impossible.
  37. W Says:
    September 21st, 2007 at 5:39 pm The conclusion is just what I always assumed: Rip was never ripe nor mature to be a Hahahavrad student, but just used his blog to pretend that he was one. Too bad.
  38. Retread Says:
    December 28th, 2007 at 9:08 am Start gnashing your teeth organic synthetists. The humble cyanobacterium Anabaena PCC 7120 makes a C18 fatty acid carboxylic acid methyl ester which contains a bicyclo [1,1,0] butane moiety on the other end. The paper contains no speculation as to what the organism does with it, but lots of hypotheses as to the biosynthesis starting with a linolenic acid hydroperoxide at C9. [ Proc. Natl. Acad. Sci. vol. 104 pp. 18941 – 18945 ‘07 ]


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