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The Thoughts of George Whitesides, Part I

A number of readers have mentioned this new paper by George Whitesides on organic synthesis. I can state as a fact that the first time I heard a joking reference to his attitude towards traditional synthetic organic chemistry was in the summer of 1983, so it’s not like he’s been keeping his thoughts bottled up. But this is certainly a good summary of them, and here’s the key question that’s being asked:

. . .The ability to put together molecules – bit‐by‐bit, simple or complex – is one of chemistry’s great accomplishments, and a source of amazement to those in many other fields of science. More than one physicist has told me that s/he cannot believe that it is possible to manipulate bonds between individual atoms with the skill that organic chemists do. When I look at a complex structure assembled in a beautifully organized campaign, I also am amazed. That said, all fields of science morph with time. The phrase “organic synthesis” has come to mean “synthesis of structurally complex natural products”, or, perhaps, “synthesis of complicated molecules with pharmaceutical activity.” Nature, and relevance to healthcare, define the targets, and provide the utilitarian justification for the effort. Is there (or should there be) more to it than that?

Subsidiary questions are whether organic synthesis of that sort is worth the effort that’s being put into it and whether it trains students to do useful things and whether other types of work could do a better job of that. In order to address these, Whitesides notes, we have to make sure that we’re talking about the same things. He defines “organic synthesis” (small letters) as any sort of putting-together-of-organic molecules, and “Organic Synthesis” (with the capitals) as the sort of complex and often natural-product-based synthesis practiced by R. B. Woodward, his contemporaries, and his intellectual heirs. The latter is what many people mean by those two words, to be sure, and Whitesides has some questions about just what it is.

Is the field a science that generates new concepts and new theory? Is it instead more of an art form, driven at least partly by aesthetic choices (that can be appreciated by skilled observers) rather than utility per se? Or is it something of a craft, achieving its results (in the end) through skilled empirical tinkering? These questions, especially in the way that they’re phrased, are likely to cause intense annoyance in some practitioners. But I think that the annoyance is a sign that these categories are uncomfortably plausible and recognizable.

Of course, the field partakes of all of these characteristics, but on what proportions? I think that the science/craft distinction is actually one question, and that these are on the same scale with opposite signs: the more solid the theoretical framework, the less Edisonian tinkering. My opinion is toward the Edisonian end. Organic synthesis is not bereft of theories and organizing concepts, but they do not operate strongly enough (that is, in a detailed enough fashion) to allow us to predict (for example) reaction conditions. That’s why we do this. The same goes for predicting new reactions, which is why we do this. No one sat down a few decades ago and said “Y’know, my knowledge of organometallic chemistry allows me to predict that palladium, in particular, will show oxidative addition/reductive elimination behavior that will be spectacularly useful in carbon-carbon bond formation. And while I’m making bold predictions, you might try aryl boronic acids for that reaction first, even though hardly any such things have even been described”.

As for art, I would very much like to have a dollar for every total-synthesis person who has talked about the field in terms of its artistic qualities. We have Woodward to thank for this – the man was a tremendous scientist, but his influence has not always been for the good. I don’t think nearly as many people went into spasms about elegance and beauty in reference to total synthesis before him, and what’s more annoying is that those are valid concepts to apply even if Woodward sometimes came across like an Aubrey Beardsley aesthete about them. My own view is that we should let the artistic qualities of organic synthesis, which exist, speak for themselves. Because if they can’t, no amount of raffiniert gushing about them will substitute.

Whitesides isn’t through. That three-parter is just his first of three questions! The second one is a two-parter: is organic synthesis best thought of as an enabling technology to do things (such as make drugs, etc.) or as a framework that lets us ask questions about the nature of molecules and their behavior? That is, are the uses to which we put this field, and the justifications we give for it, best described as practical ones or intellectual ones? We tend to haul out the former first and start talking in better-living-through-(organic)-chemistry style, and that’s understandable. Compounds made through organic synthesis, and available through no other practical means, are crucial underpinnings of the modern world. If we’re not proud of that, what are we to be proud of?

But that second justification, while it sounds like more aesthetic hand-waving to the lay public (and to funding agencies), has some staying power. Ask the physicists, or even the mathematicians. Asking fundamental questions, and having the right framework in which to be able to ask them, can pay off hugely even from the practical end, intellectual satisfaction aside. There’s a lot of number theory that was just another ornament of mathematics until it became vital for modern cryptography and secure communications (G. H. Hardy would have been horrified). Relativity was a fantastic intellectual feat by Einstein, but relativistic corrections are needed to make the GPS system work correctly, among many other things.

The third question is, what should we teach chemistry students about the field? That is, what are the most important things for them to know? There’s a massive pile of empirical knowledge, famously dreaded by sophomores, but it’s taught (or should be!) according to general organizing principles – although those are the very ones that are not quite adequate enough to explain everything that’s going on. At what level should we teach this subject? You can say “Here are reactions that depend on alpha-carbonyl anions, and here’s why they happen”, you can say “Time to learn the difference between the Dieckmann and Claisen condensations”, or “Here are the kinds of products these reactions form and what they’re used for”, or “Here are some tips on how to run these things at the bench”, and on and on. What should be in the syllabus?

My own take on this is that there should definitely be a bias towards the general principles, which is what the better organic chemistry professors already do. Teaching the subject as a pile of reactions is a crime. I may be too loose about this stuff, but I would rather a student, if it came down to it, mess up a bit on the detailed mechanism of the Mitsunobu reaction if they understand that its driving force is the thermodynamic sink of triphenylphosphine oxide formation. The difference between the Dieckmann and the Claisen condensations is that the former is intramolecular and the latter is intermolecular, but I think it’s a waste of brain space to give them different names and memorize them as such. I would much rather that a student, in this case, immediately recognize the mechanism of an alpha-carbonyl anion attacking an ester carbonyl (no matter what the name associated with that process is) and recognize the influence of the leaving group of the ester, the stability vs. reactivity characteristics of the nucleophile, the likelihood of the various ring sizes being formed in the intramolecular reaction, etc.

I have nowhere near exhausted the Annoying Questions of George Whitesides, but this post is long enough as it is! Look for Part II tomorrow or the next day. . .

75 comments on “The Thoughts of George Whitesides, Part I”

  1. luysii says:

    As you note Whitesides and others have been saying this for years. As a former Woodward grad student, I was shocked to hear this sort of thing for the first time — in 2007 — https://luysii.wordpress.com/2011/03/01/what-would-woodward-say/.

    But aside from thinking about the best way to teach it, organic chemistry has another function, namely exposing pre-meds to the type of thinking they’ll need to acquire — reasoning about important things based on incomplete and sometimes conflicting information — here’s why —

    https://luysii.wordpress.com/2009/09/01/why-organic-chemistry-should-always-be-taken-and-passed-by-pre-meds/

    1. Anon says:

      Premeds couldn’t care less about organic chemistry. All they want is their A’s.

      1. luysii says:

        Anon:

        Perhaps, but if they can’t pass it, you don’t want them taking care of your mother.

        1. Jonathan says:

          Why would I care if my mother’s oncologist did well in organic chemistry? Sorry, but that’s plain ridiculous. Organic is a weeder course. No better a predictor of physician aptitude than the SAT. Future physicians are much better off spending their time as undergrads learning things that would help them connect with patients and understand clinical research.

          1. Hap says:

            Biochem’s kind of important for doctors, though, and underneath it all is organic. (This review is a pretty good summary – the choices of the molecules that make living things go is dependent on basic chemistry principles.) I don’t think organic or biochem knowledge is in everyday use by doctors, but it’s not irrelevant, either.

          2. Says a chemist says:

            A prof I had (a chemist working for the pharmacy department) liked to talk about this department review they did. Basically they looked at the course grades of every student who made it into medschool at my University. What they were trying to do was correlate which class or classes that were pre-requisites had grades that correlated well with good outcomes in medschool once they were in. For instance, if they aced intro math, did they later become a good doctor? Organic Chemistry had the strongest correlation of any of them.
            You can debate why this is. I am sure practically speaking doctors only ever need to be vaguely familiar with O-chem. No argument it is used as a “weed them out” type course.

            There is a right answer to every question on the SAT. Having an encyclopedic knowledge of facts does not mean you know which ones are relevant to the situation at hand or how to apply them in the real world. Which is a large part of what doctors do.

          3. luysii says:

            “There is a right answer to every question on the SAT. Having an encyclopedic knowledge of facts does not mean you know which ones are relevant to the situation at hand or how to apply them in the real world. Which is a large part of what doctors do.”

            Exactly. In addition, the facts (data) you wish you had when confronted with a patient may not exist. You need to reason by analogy with the available facts at your disposal. Even worse, the facts may be conflicting. This exactly the sort of reasoning power organic chemistry develops — which is more important in a given case, solvent effects, steric hindrance or electronegativity? Patients do not neatly fall into categories, exactly the way reactions are neither Sn1 or Sn2.

            In the link all this sort of thing is brought to bear on the question of how you would treat Supreme Court Justice Sotomayor, a juvenile diabetic, had she come down with the flu. https://luysii.wordpress.com/2009/09/01/why-organic-chemistry-should-always-be-taken-and-passed-by-pre-meds/

            This is why even a great memorizer has trouble with organic chemistry. They can’t extrapolate what they know into the unknown, and if they can’t do this well they don’t belong in medicine. No matter how long you practice, you will deal with clinical situations you haven’t seen before and which aren’t in any book.

  2. Thatchemistkid says:

    The timing of this post is very interesting, was it a purposeful response to the ( https://pubs.acs.org/doi/10.1021/jacs.8b02266) editorial by Prof. Baran published yesterday or was it just coincidence? Prof. Baran did cite this blog several times in the editorial.

    1. Natural Chemist says:

      Did he pick a lot of syntheses from his former students/postdocs for this virtual issue or am I just being overly critical?

      1. Donato Lyuba says:

        Those are the people in his tight little world. It was such a sad editorial, too. Natural products total synthesis: it’s cheap, kids love doing it and they get good jobs from pharma. What an inspiring case for a sub-discipline!

      2. Petinga says:

        No you’re not being overly critical. Baran is too imbued of himself to avoid overhyping the achievements of his scientific offspring.
        That editorial is indeed a sad little piece.

        1. David v. Goliath says:

          Basically it’s an extended, insufferable humblebrag.

          I find Baran’s public intellectual aspirations much outstrip his charismatic abilities. Just compare his editorial to Whitesides’: regardless of whether you agree more with one than the other, one is written thoughtfully and with some real scholarship, while the other is a simplistic polemic written with equal parts bluster and denial.

          Baran is a great organic chemist, but certainly not the visionary savior of the field he considers himself to be.

          1. Mol Biologist says:

            Great post! I used to hear this particular joke many times during my studies college. The education is what’s left when you forget everything. However, how your neural connections will be wired is ONLY your choice. It can be countless hours of consulting for pharma or “the unique challenge which chemical synthesis provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both”. My two cents is on the side of doctors who are well trained in biochemistry and can understand the adverse metabolism of the individual patient, especially for clinical trails design.

      3. tlp says:

        He also considers his countless hours of consulting for pharma as evidence that organic chemists are still in high demand. Which is kinda telling…

        1. Hap says:

          Don’t know if it means they’re in high demand, but it likely means that there’s some set of things that they would like to do but can’t, or that require knowledge that they can’t get another way. It does put a lie to the idea that people can make anything they want. I’m not sure it says anything about the job market – they may be hiring Baran to consult because they don’t want to have to hire and keep people around long enough to get that kind of knowledge of synthetic chemistry, or to gain enough knowledge in that area of expertise.

          I don’t know if making natural products is worth the cost – it makes neat stories, and sometimes you find cool stuff (Eribulin), but lots of the time, people don’t deliver what the ostensible purpose of the exercise was (if you’re going to prove a structure, you don’t need much, but if you’re claiming people can make analogs using your route, you’d better be able to deliver more than a mg or two). The interests of people publishing methodology papers and of people who would use the methodology also seem to diverge (A: We won’t use chlorinated solvents. B,C,D,….Z: Look at this neat reaction we made that only runs in 1,2-dichloroethane!) To get good methodology, it seems like you need to fund a lot of not-so-good methodology work.

          Particularly if you’re making methodology, I’m not sure when function should come up. The point of developing methods is to allow other people to more quickly make molecules that do something they want – we don’t ask shipbuilders to be explorers, too (though a sailor’s knowledge would not be amiss in shipbuilding). If you’re spending a lot of time making a big natural product, though, then you probably need to consider why you’re making it, so that you know what you need to do to fulfill the purpose. If you can’t do what the point of the synthesis is, then total synthesis of natural products is like expensive mountain climbing. At that point, funding agencies have to wonder if mountain climbing is cool enough or useful enough to fund for what it costs.

          1. Clipper says:

            “we don’t ask shipbuilders to be explorers, too ”

            We do, however, ask shipbuilders to build ships. I have the impression that if most academic organic chemists were shipbuilders, all we’d have is a giant pile of oddly shaped lumber.

          2. Hap says:

            I don’t know – it seems like people have come up with lots of useful reactions (maybe not as good as hyped a lot of the time, but not the suck). For example, if people are complaining that your reaction is so easy to run and make stuff with that it is undiversifying compound pools, I think it’s safe to say that you actually did make the chemistry equivalent of a ship.

    2. Derek Lowe says:

      Baran’s article will be coming up in the follow-up post, fear not!

    3. anon says:

      Baran’s editorial is so full of hysterical praise of organic synthesis that it fells like it must be satire.

      1. anon says:

        barf. at least there were no greek mythology references this time

        1. Anoni says:

          he’s still doing that to suck up to KC. *eyeroll*

  3. Sanjay says:

    Much as I have admired Whitesides, this post seems a bit lost in time. As far as I can tell, the “click” chemistry/bio-orthogonal folks are rewriting the idea that organic synthesis implies synthesis of very complex molecules; rather, they assemble simple things with the complexity shunted off to issues of selectivity and reaction conditions. That idea is hardly a hidden one right now!

    1. Unchimiste says:

      Fully agree with you. A lot of things Pr. Whitesides is calling for are actually coming on. When I was a PhD student 15 years ago, JACS was full of “Natural Product/Total Synthesis” papers. Now, although there are a few exceptions (Baran…), there are way more material science and chemical biology papers in JACS than papers on total syntheses of complex natural molecules.

  4. RAM says:

    Gotta love the time it took from submission to online publication

    1. some fool says:

      Why would that matter for an essay, which is not (usually) peer-reviewed?

      1. tlp says:

        …especialy if it is (likely) invited

        1. RAM says:

          Where did I say that it was bad?

  5. Some idiot says:

    Bravo regarding general principles!!! It peeves me no end when some people say that if you don’t know the name of a certain reaction then you aren’t a proper chemist… Yes, the existence of names can aid communication between chemists (but only up to a point…) but that is but a shadow compared to a deep understanding of chemistry and why chemistry happens…

    🙂

    Reactivity is Electron density and Geometry, not names…!

  6. Bagger Vance says:

    Whitesides has a point–“The Industrial Revolution and its consequences have been a disaster for the human race.”

    1. Peter S. Shenkin says:

      Civilization and its discontents.

    2. Humans says:

      Define “human race”

    3. Anon says:

      My humble judgement is that furious pace of synthetic organic chemistry starting early eighties with asymmetric reaction followed by equally break neck speed of medicinal chemistry starting late eighties pretty much decimated this branch that threw many people out of their jobs that paid decent salary! We can only reminisce the glory days!

  7. (No)name Reaction says:

    Absolutely agree on your last post, Derek. I had the traditional organic synthesis upbringing and I was always appalled by how so many of my colleagues measured their own and others’ worths by how many obscure name reactions they could rattle-off and sketch on the board. Junior students were severely castigated for not getting the name just right, even if they could push the arrows perfectly if given the starting material and product.

    I’m glad to see this idiotic macho culture of organic synthesis is on the decline now, but it still gets my hackles up when some arrogant postdoc from a “hardass” lab tries to perpetuate the old ways.

  8. 123 says:

    Name reactions are part of organic chemist’s language, like it or not. They are there to help (ofcourse to credit and recognize the inventor) than to hinder with student’s’ learning. They also help with organization of vast knowledge in simple and easy to remember, recall and apply ( Ex: Diels-Alder…people recognize that it needs a diene and oenophile , heat, 6 member-ed ring formation, concerted reaction mechanism). A reaction does not become a name -reaction all of a sudden overnight unless it is reproducible, reliable , time -tested and a worthy enough. Once the reaction mechanisms/principles are taught, students ought to be trained to associate them with the name reactions in their learning of vast body of knowledge such as organic chemistry. My 2 cents.

    1. 456 says:

      A diene and an oenophile? I wondered why my Diels-Alder wasn’t working – I’m obviously not drinking enough!

    2. Some idiot says:

      I take your point, but I still mean that it is far more useful to understand how/why (eg) electrocyclic reactions work rather than who discovered it… Perhaps for a few major classes it can be useful, but it is it really relevant to learn all of the names? To be honest, (as an example) I cannot remember the names of all of the variations on the Wittig reaction. However, I know and understand the chemistry of them all, and when and why one is more useful than the other…

      My two cents..! 🙂

      1. Hap says:

        If you know enough to find the reaction names, then it’s better to understand them than name them. In lots of communication, it’s hard to summarize reactions quickly without names, and so knowing the names can accelerate communication.

        If you’re stuck on a desert island, then you’d have problems, but you’d probably not be doing any synthesis (or discussing it) anyway.

  9. moving on says:

    Regarding the training of synthetic chemists: I took a psych class for fun, and it was interesting to read the very long section in our book about how to test a hypothesis. In psychology, it takes a lot of creativity to design a proper experiment and controls. I realised that in synthetic chemistry there basically is no experimental design. There’s no statistics. There’s no data interpretation. Just a yield, and you only need to make the reaction work once. The field is over taught, and past its exciting prime.

    1. AVS-600 says:

      I don’t think organic chemistry has ever required much in the way of statistics or data interpretation, even during whatever you would consider to be its exciting prime. That doesn’t mean anything about the field in and of itself, other than that our data tend to be really, really easy to interpret compared to other disciplines.

      1. Thermo says:

        The number of molecules in a reaction is larger than the mice used in animal model study. Thermodynamics is already statistical.

        1. AR says:

          More than all animals studies ever conducted…

          1. Dr. CNS says:

            Maybe that explains the typical JMed Chem table of IC50 or cLogP values with 4 significant figures…

      2. movingon2 says:

        My impression was that way back in the 60s-70s, there was more physical organic chemistry taught, and this was slowly dropped and replaced with name reactions. I think a physical organic chemist has a broader set of scientific tools to work with.

        Its a bit interesting to see what synthetic chemists do, or think they can do, after a big layoff. Its not pretty, and rather unnerving.

        1. Hap says:

          I think that’s because there was more funding for phys org then – it went away and became funding for synthesis, and probably will change when synthesis funding is reduced to go somewhere else.

    2. Thatchemistkid says:

      I am not sure about this. I have many times worked my way out of trace yield and almost complete decomposition by judicious reaction design while actually still using the same set of reagents that initially gave me decomposition. I do not screen conditions for the sake of screening them? I carefully and deliberately choose each condition…. I don’t know what level of experimental design is needed in psychological experiments..the number of possible situations may allow for more creative experiments.
      It is though, kind of ridiculous to say that there is no experimental design in our field???

    3. Angus says:

      It’s true that the design of experiments in synthetic chemistry is relatively straightforward and that statistical methods are rarely required, except for optimisation of multi-variable systems (DoE methods). There are numerous weighty tomes describing research methods in the social sciences, due to the complexities of measuring human behaviour. Is there any book on ‘research methods in chemistry’? Would a short book on this topic be useful to students as they embark on research in chemistry? The dominant model for training chemistry researchers is the apprenticeship model, in which grad students mostly acquire research skills by ‘osmosis’. Is there a place for a more systematic training in research skills?
      However, devising hypotheses for efficient synthesis of targets remains very challenging, partly, as Derek points out, because of our limited ability to predict reactivity. Whitesides’ comments about Organic Synthesis in the tradition of Woodward et al. are well made, but some training in the design and execution of multi-step syntheses is still a valuable preparation for many careers, as well as being intellectually satisfying.

      1. Robert says:

        There is actually an interesting book on the application of statistical experimental design in organic synthesis. “Design and Optimization in Organic Synthesis” by Rolf Carlson. From the description of the book on Amazon:
        “The methodology is based on multivariate statistical techniques. The following topics are treated in depth: classical two-level designs for screening experiments, gradient methods (steepest ascent, simplex methods) as well as response surface techniques for optimization, principal components analysis and PLS modelling. The book is intended as a hands-on text for chemists and engineers engaged in developing synthetic methods in industrial research, e.g. in fine chemicals and pharmaceuticals production, as well as for advanced undergraduate students, graduate students, and researchers in an academic environment.”

        I think it was Svante Wold who directed me to this book quite some years ago as a result of taking a short course (ca. 3 days) from him on multivariate statistical analysis.

    4. ProcessChemist says:

      I did not do total synthesis as a grad student, but the single best continuing education course I took once I was employed was Experimental Design (offered back then by DuPont). It was like a new world opened up to me, I never heard anything like this during my Ph.D. or postdoc studies. Also, Mark Halpren’s phase transfer course was exceptionally useful (I still reference the workbook 20 years after taking it).

      1. Anonymous says:

        Do you have any notes or list of books that you could share from your “Duponts Experimental Design” course?

    5. Barry says:

      by the time you can detect and characterize* the product of an organic reaction, it has worked billions if not trillions of times. The relevant statistic is not how many times you set up your glassware; it is how many times the reactants found each other. The statistical analysis at this point is a sterile exercise.

      *except for people observing chemistry in e.g. the mass spectrometer

      1. Some idiot says:

        If you are referring to DoE: not so… I have seen and been involved in quite a few cases of process optimisation where subtle (and useful) mechanistic effects were first detected during the DoE runs, precisely due to the “sterile statistics” (and therefore very carefully controlled control experiments). It is a very useful tool (in the right situation). 🙂

      2. Noway says:

        This is an insane argument. The corollary is that if you treat one mouse with a drug and another with vehicle, take out a kidney from each, and run a western blot to compare levels of a single protein, that your observation/the effect has been “reproduced” millions or billions of times. What a joke. Same guys that whine on biology for statistics and methods somehow trying to skirt the fact that synthetic organic chemistry is indeed void of common reproducibility metrics. Come on.

    6. anon says:

      Psychology experiments are severely limited by the approaches that can be used on the subjects( people). The so called creativity is a method to circumvent this limitation.
      Heavy reliance on statistics indicates that the experiment can not be conducted in an ideal situation. The absolute truth from pure science should be “black and white”. It should do away with statistical significance altogether. It should not require a magnifier to see the difference. E=mC^2 and Newton’s laws never needed statistics.
      Using statistics is a sign of soft sciences (social science, biology) where conclusions can be not definitively made and correlations sneak in to replace causal-effect relations. According to Joseph Needham, relying on correlative evidence is why the Chinese failed to develop science.

  10. NEChemist says:

    Why exactly does everyone insist on the complete BIO-ification of organic synthesis? All my friends who make new molecules every day in the lab that have nothing to do with pharma, scuba diving, or jungle expeditions would be interested to know that what they do isn’t defined as “organic synthesis”.

    1. anon says:

      because this blog is mainly a medicinal chemistry blog and a lover of biotech. what do you expect?

  11. MoMo says:

    I had a Major Name Post-doc come through my company on an interview sometime ago- they thought they were the cats’ meow. Nobody liked him as the arrogance was stifling, and he praised the virtues of total synthesis of complex natural products- which I listened to but with a raised eyebrow. We offered said genius a job, and when he showed up couldn’t synthesize even simple esters, amides let alone get a Suzuki coupling to work.

    Major name Post doc was fired, and last I heard he went into analytical chemistry, a safe place for a person with all thumbs.

    Moral of the story: Natural Product Synthesis is marginally useful, diversity of chemistry reactions performed and skills are more desirable compared to narrow-field synthesis, and the only reason some people are even marginally employable is because they have a PhD- even from Big-Shot academics. And don’t be arrogant- you’ll be toasted and tossed.

    1. Phellatioredox says:

      O a macmillan student? They’re good for replacing your screening robots 🤖

  12. Azetidine says:

    Any name reaction with more than four syllables is not worth memorizing, and usually not worth doing. You can always find another way.

    1. b says:

      Sonogashira?

  13. Mister B. says:

    Total Synthesis was my first love in chemistry… Something I have seen missing, are the skills (at the bench) that are needed to complete properly the desired natural product you aim.

    Despite my synthesis was not completed*, I know that the skills I developed are useful. I’ve become more careful on the reaction design, I have come to know more about reactivity (and unexpected one too), also worked on different scale, when compounds properties have reach a crucial point etc.

    Ph.D. can be seen as a training and to me, total synthesis is still the best of it. But, it doesn’t add any value to Science. It just brings better scientists to the point they are capable of running their on projects with a critical point of view.

    * I was so naive back to my beginnings … Total Synthesis is a cruel mistress. No synthesis completed, no reward. No reward … What’s next ? This thought is closely related to the infamous “publish or perish” moto, way of life in the academic.

  14. Uncle Al says:

    Discover deep thermodynamic holes (adamantane makes itself) and grotesqueries ([1.1.1]propellane’s p-p single bond ). Accepted theory alone cannot create science (physics’ past 50 years). Concatenate insubordinations.

    Azatriquinacene plus diborane suggest 2-aza-9-bora-D_3-trishomocubane. Axial distance is too long for an internal frustrated Lewis pair (maybe). Axial compression?

    http://www.mazepath.com/uncleal/dipole3a.png
    … It reversibly self-polymerizes to quaternized dipoles.

    Electrostatic axial compression! If that is an internal charge transfer spinnable ambient temperature superconductor, good enough. If you like small molecules, append a methyl front and back (or split hydrogen). Look.

  15. Doug Steinman says:

    When I worked as a TA I taught a number of premeds. And yes there were some who were only interested in getting their A’s. However, I did see quite a few of them who were quite interested in the beauty and complexity of organic chemistry. When my mom got sick and was spending a lot of time in and out of hospitals, I found out the the doctors who gave her the best care were those who told me how much they enjoyed organic chemistry. The subject came up after they found out that I was an organic chemist. I am not sure that this is a universal phenomenon but it certainly was my experience.

  16. GladToMoveToProcess says:

    Yes, the heroic days of natural product syntheses are largely past. Still, trying new reactions on complex molecules leads to a better understanding of those reactions. It’s a bit like natural product determinations in the pre-nmr/pre-xray/pre-whatever days. Those studies led to lots of new reactions. Of course, sometimes they led the chemists of the day astray: I think that in one of Stork’s enamine papers, he suggests that nobody had tried alkylating (or something) enamines because some degradation product, maybe from strychnine, was unreactive. Anyway, natural product syntheses are fun to read!

  17. Anonymous says:

    Prof. Whitsides did not say in his rather outdated article that “Organic Synthesis” is not required any longer. He just wanted everybody to embrace the “function” part as well in addition to the “structure” and “Aesthetic” aspects of it. I do not think even Baran’s lab that all of you seem to be critical would do some total synthesis for just the sake of synthesizing unless they can come up and/showcase some cool methodology or reagents. His lab has generated a lot of useful methodologies and reagents, and trained a lot more independent PIs than any of his critics have done.

    Agree that the final compounds are often made in mg quantities in total synthetic campaigns, however, that suffices to show that given target succumbed to the creativity of the Organic Synthesis community. It would only be matter of months to scale-up the synthesis to grams even if it took 5 years to figure out the required chemistry to make a mere 1mg of the target (It is akin to lay a path/road…it takes time initially to engineer and lay it out; once it is in place it can be used for ever!).

    Agree that people should not be just making the natural products and forget about them or wash them in to drain after they are made in such a laborious and expensive way. I do not think anyone is doing that any longer. People such as Prof. Matt Shair have embraced the “function” part of them and are taking those NPs and their analogues to analyze the SAR for their biological activities, to understand their chemical biology ( mode of action, target etc…. …there would not be MTAR, other drug targets and/or other drugs such as vancomycin etc that we have now had it not been for Organic Synthesis…true later on they might be just cultured; you need to isolation people who are again good organic chemists to isolate useful drug like compounds from the sources to be able to culture).

    If still oppose, I would think the Organic Synthesis community would be happy to embark on synthesis of molecules with “function” if other folks (especially those who are very critical about the field and if they are capable of doing so! ) can design the same. Of course, it is not easy to do so i.e., designing or developing the molecules with the function, the critics take off on Organic Synthesis people who are forging with whatever they believe is meaningful to make by toiling in the labs i.e., they believe that the natural products are worthy targets with the function. Period.

    It is arduous path even for the hardcore practitioners of Organic Synthesis to train the graduate students and to get them to a stage to develop methods to make the decent molecules as the quality and commitment of graduate students is not the same as what was available to WOODWORD . The students are not going to be useless as the skill set is transferable and capabilities ( synthesis skills, OCHM knowledge, trouble shooting skills, dedication and determination) to make complex molecules is not that easy to come by and even if short sighted pharma industry lay them off in favor of outsourcing. So, in short, cut some slack for the Organic Synthesis community.

    1. Hap says:

      1) Particularly with the longer syntheses, I don’t think scaleup would take only a few months. Knowing the route and what works and doesn’t is likely to help, but reactions in a synthetic route likely have been done only a few times (or once), and involve conditions which don’t necessarily scale well (heat transfer) or reagents which you maybe don’t want to scale up. It took a long time for discodermolide syntheses to be scaled, for example. It depends what you want to do, though. If you state your synthesis is amenable to making analogs, then you ought to have done the synthesis on big enough scale to make analogs without someone else having to scale it up for you – that was why you said you were doing it. Boekelheide noted this a long time ago.

      2) If synthesis is there to train people, then you have to compare outcomes and costs – nothing in science is cheap, but you’d like to train people most effectively. Making a big molecule isn’t cheap (brevetoxins, taxol, etc.). Did the skills people learn doing it make something that couldn’t have been done otherwise? Would the people who did it have been successful anyway?

      3) Whitesides has big labs, and has had lots of post-docs, and a lot of PIs have come from his labs.

      1. Anonymous says:

        You got me wrong. I had no issue with Prof. Whitesides as a researcher and I agree with you that he has produced a lot of good scientists. However, I have an issue with him poking his nose with “Organic Synthesis” people when his lab is run by organic synthesis ( he would not be able to do what he intends to do without the skillset of organic synthesis!) as he admits. It is akin to cutting the branch of the tree that you are sitting on! Organic Synthesis people never weighed in with their free opinions as to what medchem or material science people should be devising and doing. How would you fare if you are asked to design potent ligands each time you start a synthesis? Organic Synthesis has a lot of utilitarian value than waht many NIH funded irreproducible biochem/medhem projects do. Why do you people have issue with other fields when you are not living up to the bill?

        1. Hap says:

          1) Except you don’t need very complicated synthesis to answer useful questions. Making maitotoxin is unlikely to lead to anything that helps people answer questions. If you don’t know where to go, buying a Maserati to get there makes little sense.

          2) How do you tell if total synthesis is useful training compared to other methods? You can compare people that do total synthesis to methodology people, since often they’re in the same groups, but how do you compare it to other ways of training people?

  18. Javis says:

    I know this will be poorly received, but man whitesides is stupid. I dont know he got his name on some of the tech he took credit for ( probably a few sharp grad students or postdocs ) but the man himself is a moron.

    1. Some idiot says:

      “the man himself is a moron”
      Just curious: why do you say that? I have met him a few times, and had a good discussion about stuff… He always seemed to have a good deep feeling for things, and certainly never seemed superficial… so I am curious as to why you say that…?

    2. dumber&dumber says:

      If you have met Whitesides, you would realize that you probably is the moron. He is a rare visionary with a lot of information.

  19. UK Chemist says:

    So is the issue about variable academic quality.? If so is this any different between the good and bad projects in other branches of science e.g variable/dubious med chem projects funded by NIH and Wellcome Trust? So why pick on natural product synthesis as opposed to any other discipline?
    I think Pious Harvard professors should focus on things they fully understand. One bi-product of total synthesis is that it has created a large group of small molecule drug inventors. Not sure how many material scientists would be on that list.

  20. DrOcto says:

    A PhD is an opportunity to learn a craft in as close to real world conditions as possible.

    A total synthesis is a neat way to force a grad student to undertake a wide variety of reactions in practice and learn a lot of chemical theory. They will learn very quickly if this is something that they would like to do for a living.

    Very often in a long route the student will encounter something unexpected such as an undesired side reaction, wrong product, or intermediate that does not react at all. These situations force the development of new solutions, new reactions, optimisation of existing conditions. i.e. they contribute to the growing understanding of a vast unexplored chemical space.

    If the student is very fortunate, they may finish their long winding route and deliver 20 mg of the final natural product for confirmation of stucture and evaluation of biological activity. This is the justification for the synthesis on paper and in funding applications, but it is not where the value of the work resides.

    As long as humans are still needed to produce molecules, total synthesis is a great way to train them to do it.

  21. Scott says:

    Being a non-chemist (I’m a Business Major, of all things, I read this blog for Things Derek Lowe Won’t Work With and How Not To Do It), I’d want to approach the subject of learning chemistry from “Here’s the kinds of things you use [reaction] to do: [list]”

    1. Derek Lowe says:

      And that (with a lot more details for all the tricky exceptions and qualifications to those lists) is just the sort of thing that I expect the AI expert systems to take over for. . .

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