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More Thoughts of George Whitesides – And of Phil Baran

The other day I wrote up some comments about a recent article from George Whitesides. If you’ve heard him speak on the topic of organic synthesis, you’ve probably heard most of what’s in that piece, but it’s a good summary of his position. Picked up roughly where I left off last time, he has this to say about innovation:

One measure of the health of a scientific field is its ability to generate new ideas (as opposed to extensions of already established themes), and to reinvent itself. A familiar idea in discussions of innovation is that it comes in different forms: for example, innovation can focus on new technology (where organic synthesis has tended to shine), or on new processes (where the most innovative work has often been done by process‐development groups in industry), or new business plans (for example, the decision by China to make low‐cost capital available for production of silicon‐based solar cells – a decision that has been enormously important in accelerating the implementation of solar energy). The question facing organic synthesis is not “has the need for new methods of syntheses disappeared?” but rather “What problems – intellectual, empirical, or practical – most require new ideas in synthesis?” Is the future for more of the familiar – what Kuhn called “ordinary science” – or for something more radical, more important, more different fundamentally? (More, perhaps, having the audacity of what Woodward, Eschenmoser, and others suggested and demonstrated 50 years ago?)

That’s an uncomfortable question, when you start to think about it. That’s not asking organic chemists what they can do, but what the most important and interesting questions are that they can contribute to. And it’s also asking, “Of the biggest and most important questions in general, which ones can organic synthesis help with?” Whitesides lists some of those in broad strokes (catalysis, materials science, synthetic biology, automation/mechanization of organic chemistry, etc.) and in more particular ones (molecular recognition, origin of life studies, sequence-specific polymers, new biocompatible materials, and more). It may or may not be a coincidence that what many people think of when they think of “organic synthesis” – total synthesis of natural products – does not impinge nearly as much on these topics as some of its practitioners might think.

So what are the most important questions that natural products synthesis can provide a key role in helping to answer? One that I can think of is unraveling complex biochemical pathways where more simple chemical matter just doesn’t seem to be able to make things clear. I would adduce rapamycin and FK-506 as examples of this, and there are many others. Indeed, some of the larger pharmaceutical molecules are getting into “non-natural-product” zones of complexity and molecular weight (although, to be sure, they’re generally much easier to make, since we’ve produced them (or their precursors) with that in mind. Modifications of the natural products themselves is another such field, and it’s not an easy one, either.

These are worthy topics, and there are others. But at this point, I want to being in another recent article, from Phil Baran at Scripps, introducing a special collection of total organic synthesis papers. This introduction is written by someone who’s well acquainted with criticism of the field. Interestingly, he and Whitesides are in agreement on what some of the interesting problems are (automation being one example), but that agreement definitely doesn’t go all the way. That’s because Baran’s article, as mentioned, is deliberately written as a defense of total synthesis, and it reads at times like a response to a prosecutor’s opening statement.

I agree with some of what Prof. Baran has to say as well. I think, for example, that he’s absolutely right when he says that the application of AI and automation to really complex molecules is still a long way off. We might disagree on just what a “long way” measures out to, but there’s no doubt that retrosynthetic planning of such molecules and their actual forward synthesis is a really significant challenge that only humans – and pretty damned competent humans, at that – are now able to meet. (Drug-sized molecules are another matter). Of course, Prof. Baran and I are in agreement about many other points as well, a big one (mentioned above) being the use of such complex molecules to work out biochemical pathways. There’s often no alternative, and there are several fields that would be in much worse shape if synthetic chemistry hadn’t evolved far enough to deal with such structures.

The key place where I think Baran and Whitesides, though, do not really come to a meeting of the minds is in the question of “Why?” Some of the responses given in Baran’s article – total synthesis trains students well, industry likes to hire people who do it, it’s a solid way to prove compound structures, it’s beautiful in and of itself –  are the same justifications I was given when I was first working in the field in the mid-1980s. And it’s not that time has falsified all of these, but it may have made some of them a bit less compelling. It may seem odd to say it, but for some time I bought into this worldview completely, and even now I don’t completely reject it. But sometimes, I think it seems to the total synthesis community that you’re either for them or against them, and that apostasy is always a short, fatal, step away. The shortest and most fatal of those steps is wondering in general if total synthesis of natural products still pays its way, scientifically. Here’s Whitesides again:

. . .The trick will be to find classes of problems that return complex synthesis (Organic Synthesis, perhaps in an evolved and more expansive and ambitious form) to a central role in the future of the field, rather than having it become an extraordinary specialty or craft, admired but occupying an increasingly isolated place as the rest of synthesis moves on. The argument that complex synthesis, by itself, is beautiful is doubtless true, but also dangerous. Most societies have valued beautiful products of human imagination and skill, but paying to support the artists who produce them has been another matter entirely. And, unfortunately, the beauty of Organic Synthesis is not something that most non‐synthetic‐chemists can understand.

Technical expertise is not, by itself, enough to sustain a field (consider mechanical watchmaking or glass‐blowing). To prosper, Organic Synthesis must also solve recognizable problems.

That exact argument for beauty is one of the ones made in Prof. Baran’s article, actually. It’s not his main point – actually his main points and those of Prof. Whitesides might well end up being closer than you’d think – but it does represent the sort of sticking point that keeps coming up between practioners of the field and those outside it. I’m outside it, and have been for many years. I can understand it and appreciate many of its qualities, but I’m not able – unfortunately – to tell people that its best days are yet to come. They might be. But they might not.

60 comments on “More Thoughts of George Whitesides – And of Phil Baran”

  1. Mister B. says:

    May I suggest a minor adjustement to your words, Derek ?
    “Total synthesis trains students well, industry likes to hire people who do it ”

    I agree with you when it comes to training, but industry likes to hire people who succeed it ! I’ve seen many of my fellow Ph.D. student, in total synthesis, without achieved synthesis, in great difficulties after their viva ! (I will have the same issue soon … )

  2. Formergsk says:

    Total synthesis is an art mostly. There may be reactions or methods developed along the way that can have a fortuitous effect on other areas of chemistry, but I would say by and large total synthesis is a solved problem.

    Can there be any doubt that the Baran group, for example, cannot synthesize any isolated natural product we may identify? Given sufficient time and resources it’s a done deal.

    There is a certain pedigree to total synthesis due to the great old men of chemistry like Woodward and Corey, but it’s just a halo from the halcyon days. If we could wipe our minds from bias, would we really be funding as the same levels as we are today?

    1. Hap says:

      There’s lots of simpler molecules we can’t make though (meta substitutions – some Pd-catalyzed methods), and in some cases, “enough time and money” are things that people don’t have. Making things quickly and as cheaply as possible are not accomplished tasks, and methodology exploration (and sometime, total synthesis) are how you get better ways to make things.

  3. Nate says:

    I suspect AI forward synthesis is much closer than automation. As an analogy, I think of the production of car tires compared to the production of cars themselves. Cars are made on assembly lines, where the product moves and each worker (or robot) does one specific, reproducible task. (This is common knowledge, we all listened to the stories of Henry Ford and the model T revolutionizing production.) This of it as a linear synthesis in organic synthesis terminology.

    Tires for cars aren’t made on assembly lines, they are made one at a time by skilled workers who fill the molds with all of the components and produce the final product in essentially the final step. It’s basically a convergent synthesis, many different logistics chains end up exactly at one point. The skill and awareness of the operator is a significant factor in the quality of the final product.

    Robots have taken over many jobs in the auto industry, but tires are still made one at a time by trained and skilled operators. You’d think tire molder would be an easy thing to automate, and it’s a price-sensitive market, so there is plenty of incentive to do so. But it’s all of the little things you have to get just right on a not-quite replicative situation that has made this challenging. (Chaos theory plays it’s games here as well.)

    Chemistry is more like making tires, our rules aren’t nearly as concrete as you’d like for automation (as my college organic professor used to say, “it’s true except when it isn’t”) and the conditions tend to vary a little bit between runs of similar reactions. Anyone who has scaled a process knows that getting a somewhat simple reaction to give the same results without fail is a time-intensive process, it’s much worse than trying to make a good tire.

    Once we can automate something as “simple” as a car tire we might be able to approach lab synthesis.

    1. What says:

      So the best analogy as to the art form that is synthetic chemistry is producing, round, hollow, rubber? Field has major issues if that is so

      1. Nate says:

        I guess this analogy only works if you understand the intricacies of tire construction. I’m no expert in that field but I do know you have vastly oversimplified the nature of a modern tire.

        1. Bagger Vance says:

          Maybe it works if you imagine that all the bosses at the car manufacturers were trained only in tire creation, and everyone tells aspiring car makers/designers to spend years learning tire making as lowly (and low-paid students) from a handful of masters of the craft, and that they say “don’t worry about engineering, you can join a car company and learn it on the fly”, and then you get out and there’s no jobs for tire making in the US anymore.

      2. Anon says:

        It’s such a shame that supposedly creative and passionate organic chemists are not able to thrive in most areas of the majority of pharmaceutical companies. Bring on cascades, late-stage diversification and reactions that are unprecedented (ie. not featured in the usual reaction search tools); risk vs. reward! “Think outside the box – there is no box”.

  4. Anon says:

    “ synthesis trains students well..”

    Yeah because there’s no better training than screening solvents, conditions and metal salts for thousands of times for a few mg of product. You posted a paper published in Science a while back. It said they found the right conditions after about 1000 experiments. Give me robots any day.

    1. Dr Bot says:

      What you’re describing is not total synthesis. That’s methodology.

      1. Nice Try says:

        That was Baran’s Maoecrystal…which is Total Synthesis.

        Sure, you spend some time thinking profound thoughts about your route before hitting the bench, but in terms of wet chemistry you screen like everyone else for each of your steps (need those 90+ yields/ee’s so your overall yield is high enough for JACS).

        I’d argue that figuring out a mechanism for a method is at least as intellectually challenging as sketching a route, anyway.

  5. Anonymous says:

    Yes, the progress in Organic Chemistry has been incremental at best and it took us more than couple centuries to get where we are today. It’s too early to call the total synthesis is no longer required and we have all the tools and capabilities to do what we need. The tools ( spectroscopy and purification) are state-of-the art and that would enable us to find out quicker and better methods to assemble complex molecules only if the field of “Organic Synthesis” continues. Why do we expect the Total Synthetic chemists to stop doing what they are good at and ask them to solve every other problem on earth? Let’s assume that there are 10000 PI’s and $200000000 in funds to carry out research in US, why can’t we leave 100 of them to have 10000000 to do total synthesis to train the work-force ( looks like there is no ambiguity about it, at least) while synthesizing the meaningful targets ( OK…let them not talk about beauty; rather replace with difficult and enabling molecules…as it looks like the jargon that they use is what is problematic and rubbing on the wrong side of Whitesides and others). The voice and concern seems to be very negative and as though all the 10000 PIs are doing total synthesis of some useless molecules spending all the funds ($200000000).

    Would we all be happy if no body does the synthesis of any natural product at all? Where did the most of the drugs come from? From Natural products, either themselves or inspired by natural products.

    As some people pointed out, why do we want ship builders to be explorers as well. Total synthesis people are required as long as we need complex molecules and methods to make molecules.

    1. Design Monkey says:

      >Why do we expect the Total Synthetic chemists to stop doing what they are good at

      Naaah, we dont’t expect them stop voluntarily, we just shoud cut the financing of total synthesis field. By the factor of ten would be good for a starters.

      They can continue as they wish. Just in more frugal manner, ’cause results from them are not especially useful. It’s a self serving field of getting grant money and nowadays gives poor return in terms of obtained scientific knowledge.

  6. TS supporter says:

    The progress in Organic Chemistry has been incremental at best and it took us more than couple centuries to get where we are today. It’s too early to call the total synthesis is no longer required and we have all the tools and capabilities to do what we need. The tools ( spectroscopy and purification) are state-of-the art and that would enable us to find out quicker and better methods to assemble complex molecules only if the field of “Organic Synthesis” continues. Why do we expect the Total Synthetic chemists to stop doing what they are good at and ask them to solve every other problem on earth? Let’s assume that there are 10000 PI’s and $200000000 in funds to carry out research in US, why can’t we leave 100 of them to have 10000000 to do total synthesis to train the work-force ( looks like there is no ambiguity about it, at least) while synthesizing the meaningful targets ( OK…let them not talk about beauty; rather replace with difficult and enabling molecules…as it looks like the jargon that they use is what is problematic and rubbing on the wrong side of Whitesides and others). The voice and concern seems to be very negative and as though all the 10000 PIs are doing total synthesis of some useless molecules spending all the funds ($200000000).

    Would we all be happy if no body does the synthesis of any natural product at all? Where did the most of the drugs come from? From Natural products, either themselves or inspired by natural products.

    As some people pointed out, why do we want ship builders to be explorers as well. Total synthesis people are required as long as we need complex molecules and methods to make molecules.

    1. Hap says:

      They mostly weren’t from the synthesis of natural products though – in most cases, synthesis didn’t facilitate their clinical availability (discodermolide being an exception?). Being able to do chemistry on natural products is useful, and in some cases, making analogs that can’t be made synthetically gives you nice weapons (Eribulin); for the most part, though, total synthesis doesn’t have much utility in making drugs. (In most cases, total syntheses aren’t amenable to making analogs or doing much else other than proving that the target was made and, if not made earlier, the structure of the target.)

      Total synthesis helps to sort people who work hard (because they generally have to), who know lots of reactions, and can circumvent or prevail over problems. Some of these, though, are true of other studies. Synthesis is/was preferred for drug people because the ability to make potential drugs is a key skill facilitated by synthetic experience, but if that’s either not the cases or not valued as if it were, then the argument for general scientific training takes a hit. How do we know that total synthesis (or any other training) is effective at training scientists, or more effective than another method of training them?

      I think learning how to make stuff is a useful skill, and I like reading the stories, but I’m not sure that total synthesis of natural products is worth the money or effort it takes to do it, particularly on scale. For most molecules that people make, there isn’t much that they get out of making them other than the experience, and I’m not sure that there aren’t other things to do that have more intrinsic utility and would be useful for training.

      1. Pah says:

        @Hap: you wrote “In most cases, total syntheses aren’t amenable to making analogs or doing much else other than proving that the target was made and, if not made earlier, the structure of the target” and that total synthesis “doesn’t have much utility in making drugs” without any supporting evidence. There are several examples of total synthesis being applied to clinical candidates and approved drugs, including some you list, like halaven. Convergent syntheses promote analogue incorporation within the context of final compound assembly, especially when key intermediates of the larger disconnections exist in quantity. Total synthesis allows the realization of more complex natural products that could not be addressed by derivitization of isolated NP, or when promising NP cannot be isolated in great quantities. How often NP based drug discovery is pursued is a result of risk/benefit calculations of drug developers. Advances in synthetic methods and purification can lower the costs and risks of these pursuits and thus increase the impact of total synthesis to drug discovery and molecular pharmacology.

        1. Hap says:

          If a synthesis provides mg (low mg, in most cases) amounts of compound, then it’s basically going to have to be redone (likely with a lot of optimization) to make analog synthesis possible. The synthesis has told people something, but is not what it says it is. In addition, if the risk-reward calculation for making natural product analogs as drugs is in most cases for doing something else, then making analogs of natural products for drug use is not a very good justification for natural product synthesis.

          A synthesis needs to deliver what it says it delivers. Synthesis is often iterative (synthesis of the bryostatins have improved over time, to the point that they could conceivably make useful amounts of analogs), so expecting an initial synthesis to provide a final route is bad. If it’s going to take lots of syntheses to achieve the final end of analog-compatible synthesis, then the cost is significantly higher than usually stated, and the target needs to be correspondingly valuable.

  7. John Wayne says:

    I think it is great that most people aren’t doing total synthesis any more. This phenomenon has created a complete vacuum of younger folks who have a fundamental understanding of organic chemistry, making it really easy for me to obtain and maintain employment. The lack of chemistry knowledge among chemists these days is astounding.

    1. Hap says:

      Is total synthesis the only way to get that knowledge, though? I suspect that the lack of perceived value in the products of the education (because it won’t help you get a job anymore, or at least keep one) rather than the lack of ways to get that knowledge might explain why it’s less common.

    2. Uncle Al says:

      The lack of chemistry knowledge among chemists these days is astounding.” It is mandatory. Enviro-whinerism excludes training labs, diversity excludes demonstrable competence. A BS/Chem can polish lab benches using non-VOC, sustainable, CO_2-derived materials and recycled rags…except for the “can” part.

  8. me says:

    Modern synthetic organic chemistry isn’t science, it’s just bad engineering.

    90% of active synthetic groups are not concerned with discovering anything, they are concerned with inventing. That would be absolutely commendable if the inventions were honest attempts to solve real-world problems. We all know that this isn’t the case. Nearly everyone has their particular hammer and they go around looking for nails to bash.

    “Our beautiful homogeneous Ruthenium catalyst is two orders of magnitude behind current industrial efficiencies? No matter, we are doing SCIENCE!”

    No you are not. You are a poorly organized start-up company with a pet-solution and a community of like-minded people around you to act as a safety net of career awards and honorific symposia when you inevitably have zero impact on anything outside of academia.

    1. Rubarf says:

      Yup couldn’t agree more all about branding and style.

      Right font… Check
      Right color palate of pastels…. Check

      Throw together a sloppy substrate scope full of para methyl, para ethyl… off to Science™

    2. Firuza Sekai says:

      I completely agree and want to be your friend so we can rant about the deplorable state of academia together. It’s really become embarrassing to watch (especially now with Twitter providing a close-up view) and I’m mostly saddened by the students and postdocs who are paying the price. Stop exploiting people’s innate curiosity and desire to innovate and discover so that you can promote your careers and misuse the public funds! Ceterum censeo Academiam delenda est.

  9. DCE says:

    One measure of the health of a scientific field is its ability to generate new ideas (as opposed to extensions of already established themes)

    This is where you’re all wrong. Adding a different radical trap to the same reaction again and again is a major advance only capable by an excellent though leader, not just a good enough one. After all, nobody ever thought it could work.

  10. Uncle Al says:

    To what degree do “accepted theory” plus research management and financial microauditing exclude the assumed and bootlegged risks of discovery? Given Lucent Technology plus Bell Labs, hard by 100%. A chemist with a garage lab on his own nickel would be set upon by the War on Drugs, War on Terror, EPA, BATF, FBI, OSHA…local zoning codes. Academia! Grant funding.

    A housewife discovering warp drive with a simple kitchen microwave trick…would be prosecuted.

    1. DCRogers says:

      The generative grammar that constructed this Zen koan leaves me deeply moved

    2. Anonymous says:

      Exactly! They want everyone to buy a Game PC and keep playing vediogames in their basements while being supported with unemployment benefits and other social welfare benefits, however, they do not want to fund researchers that would in turn create jobs for the students and people. People will only have computers and vediogames to live with if the current trend continues.

      Moving away from supporting synthesis would be much like moving away from antibiotic drug development. You can’t discover new antibiotics when you need them and you can’t train synthetic chemists when you need them.

      OK. Let’s agree that TS is not an efficient way of to train. Could any one suggest an alternative way to train competent (synthetic) chemists more efficiently?

      1. Hap says:

        Methodology with an internship doing scale-up or process chemistry? The problem with that of course is that there aren’t many process chemistry places here (US), and lots of free (or cheap) grad student labor will mean that there would be even fewer jobs doing process chemistry.

        Alternatively, make useful molecules that don’t have syntheses; there are lots of molecules people would like to make that might give useful information if they were made or if analogs could be made easily, including some natural products. Making things because they have cool structures or because they fit the group’s methodology without having any other reason seems not to make so much sense in the presence of other targets and a finite amount of money and time, and making them in a way that doesn’t allow you to do any of the things that people might want to do with your molecules is unhelpful.

        1. Anonymous says:

          Where would you get money to do that kind of synthesis of useful molecules? The funding agencies encourage the independent methodologies to be showcased in complex molecule synthesis, I guess.

          Solution: RFPs by NIH to generate analogues of useful targets would help enlisting the important targets that all the Organic Synthesis people should focus on. Each PI should be limited to 3 or 4 projects at the max.

        2. Bagger Vance says:

          There are literally entire departments devoted to medicinal chemistry, chemical biology, translational medicine and pharmacology.

          Maybe a generation ago the “best” training for drug exploration was TS followed by learning the rest as you go, but now, why would you assume that would be better than learning “the rest” in the first place?

      2. CMCguy says:

        Although TS may not be most efficient it is IMO probably better than most other common ways to train a person for doing synthesis in industry (med or process chemist) but not exclusive route either. Of course it can be highly dependent on the PI and lab environment as not so much churning through a project but combinations of overall elements involved that add value. Typically can get greater experience across a wider range of different transformations along the way including options and alternatives. This also may mean greater time digging in the literature and reading more papers (although changed a lot since majority available electronically) plus if other people in lab tackling other molecules likewise exposes more variety in tools and approaches (where AI may benefit). Although can be lone wolf exercise a big TS do engage multiple people over time, particularly newbie intro as resupply mules, that can simulate team work and supervision skills. Frankly one major TS lesson is endurance and persistence which serves well for industry. Direct exposure with internships to industry labs and people could go a long way to development but usually a summer or even semester period will only allow acquaintance and limited real experience that can be applied.

  11. 10 Fingers says:

    My introduction to Whitesides came the day I saw him give a talk that was quite aspirational, and also punctured several hype balloons. The quote that stuck with me (probably because I wrote it down) was:
    “combinatorial chemistry was an ice-pick to the temple of the pharmaceutical industry”

    No small part of the talk was devoted to the question of “why” we *should* value in what chemistry brings to the table and what is overhyped. He was using the quote above to put combichem in the latter basket, along with a sentiment that has been characterized by others as (paraphrased, you’ll know what I mean) “Why do dogs lick themselves? Because they can.”

    Personally: while there’s still no substitute for being able to make a molecule to get the answers we need, if one can’t see *why* that should be done – or perhaps why the goal should be *making something else entirely* then you are just skilled at turning a particular crank.

  12. Curious Wavefunction says:

    To some extent what’s changed is simply a matter of degree. Yes, total synthesis is still good training but it’s competing increasingly with knowledge of other fields that required for drug discovery or biotechnology. For instance, most medicinal chemists could learn things like computational chemistry, combinatorial chemistry, molecular biology or pharmacology on the job. But these fields have become so deep and specialized now that having some knowledge of them beforehand can give people a head start. The important question is whether we want to train people deep in graduate school or whether we want to train them broad. Would I have an entry level employee who’s decent even if not top notch at complex synthesis but also knows a bit of molecular biology and programming or would I have one who has run a character-building total synthesis marathon and emerged battered and bruised but wiser?

  13. Just sayin.... says:

    Let’s be honest. Somewhere along the way, Total Synthesis became an exercise in mental masturbation to see which big name professor could synthesize the largest natural product with the most chiral centers as if number of chiral centers equated to overall IQ. Sure, they might apply some of their methodology somewhere in the middle of their megalosynthesis but the real point was to show how many chiral centers were in their final product so they had bragging rights. I worked with countless PhDs whose whole career was justified by the fact that they worked on the total synthesis of Wannawannamycin in grad school (along with 15 other grad students). Wannawannamycin is the natural product that is synthesized so that a chemist can say “I wanna be rich and I wanna be famous and I wanna never work in the lab again because I worked very hard on the synthesis of Wannawannamycin in grad school”. Their whole raison d’être was that they worked on the total synthesis of Wannawannamycin under the tutelage of some (male) professor with a really big ego. They were guaranteed a cozy office for the rest of their career with a couple of grunts or more to do their bidding while they sat in said office and contemplated the fuzz in their navel never to be exposed to those nasty chemicals again.

    In reality, nobody in the real world gave a crap about Wannawannamycin after some natural products chemist isolated it for the first time and found that it selectively inhibited some microorganism found in the bottom of the fish bowel from which it was isolated. Ask yourself how the total synthesis of Palytoxin changed the world as we know it. (And trust me, given a choice, I’d rather have a colonoscopy than hear Kishi present the entire synthesis again.)

    The inevitable pendulum swing was combinatorial chemistry and we all know how that worked out. And then somewhere along the way, after thousands of chemists were thrown to the street never to be employed in chemistry again, the egos of the organic chemist got a little bit deflated. (It often starts in the unemployment line.)

    And now we have a blog post contemplating what went wrong and how and if total synthesis still fits in. Gee, I can’t imagine. I often joke to my wife if I figure something out that I am preparing myself for the zombie apocalypse. I seriously don’t want any Total Synthesis jocks in my band of survivors. I can just see one of the other survivors putting a spear through their head when they begin a diatribe with, “Once, when I was working on the total synthesis of Wannawannamycin,………..”

    1. Unchimiste says:

      Thank you for this!

    2. Mark Thorson says:

      Funny that I was already thinking of the total synthesis of palytoxin before I got to your comment. That and the TS of vitamin B-12. Neither one led to anything, of course, but they are towering monuments to something or another.

      1. The Iron Chemist says:

        Yup, just remember to put the PI’s name first because he’s the only one who counts.

    3. Useless Molecule says:

      Reading this post just made my day! Thank you

  14. milkshake says:

    I would like to see more chemists coming from academic labs trained to think like process chemists. Multistep natural product synthesis is quite good (= much better than spending your entire thesis work on methodology within one group of reactions and with one type of catalyst) but I would like the added requirement of delivering the final natural product at least in 200mg quantity, using a sequence that is streamlined and practical. Also, I have strong bias against total synthesis projects that occupy three grad students and four postdocs for the sake of making some marine macrocyclic monster first. It was already shown that with enough brute force it can be done. It is much better to take a smaller molecule – I really like for example the work Baran lab has done on arylomycins recently.

    1. wannawannawannamycin says:

      Agree; however, the funding agencies will have to embrace the same philosophy too and encourage such ventures than wannawannawannamycin voyagers.

    2. Mister B. says:

      Have a brief look to Tom Maimone’s work (previous Ph.D. student from Baran’s lab 🙂 )
      His TS are designed to be short, efficient and most of them have produced at least few hundred mg of compounds !

  15. tt says:

    Is Total Synthesis even a good approach to accessing interesting natural products? Why not invest equally (or even more) in synthetic biology (pathway engineering) to produce these molecules…they come from nature, so why not hack nature to make them. The only possible justification for Total Synthesis is really showing a step-change in overall synthetic efficiency that could be readily scaled (things that process chemists are tasked to do). If the goal is just a few mg in order to interrogate some biological pathway, then either work on developing a bio-route or have some CRO crank through some terrible, run of the mill multi-step synthesis.

    1. MrRogers says:

      I’ve wondered the same thing. Though I’m a biologist, I can readily imagine that a combination of well-designed enzyme substrate specificity relaxation together with creative substrate design could be highly effective in both analog generation and chemist training. Such a path would also better prepare trainees to work in a multidisciplinary environment.

  16. Pfizer Joe says:

    Come on! I would like to see how many new reactions are actually used in the industrial setting. there are three common C-C making reactions that get used constantly, making amides are probably the most common reaction, putting on F from various precursors, and the rest are the reactions everyone learned in sophomore organic class. Chemists who spend their time making complicated molecules with great regio and enantio selectivity don’t necessarily make good medicinal chemists, give me a good Physical Organic chemist anytime!

    1. Dean Piper says:

      A list (or blog post) about reactions developed in the last 10 years that actually widely used by multiple med chem labs would be great!

    2. Here ya’ go, a visualization of Med. Chem. reaction types versus time. It’s informative to ask why these methodologies are used so often and use that to set that bar on new ones:
      (click link in handle)

      1. Dean Piper says:

        Thanks! Much of these seem to be reactions that have been around for a while. I was looking more for specific, recent new reaction classes. I.e. are auxiliary directed C-H activations used all the time (certainly not around here, but maybe elsewhere), phosphoric acid catalysis, gold chemistry, carbene chemistry, Rh catalysed annulations? Are there any new methods that are changing the way med chemists think about designing and making molecules.

        1. Reaction V Time says:

          Too early to tell. Even the currently well established transforms like C-N and Suzuki took a long time before they really took off. It’s really still early days on photoredox and C-H to get a feel of their impact.

  17. Nobel Jeaolousy says:

    Reason why, the current situation of drug discovery!

    Pharma industry had moved on combintaorial chemistry by cutting their natural products divisions. Now, people talk about putting the wrenches in to the wheels of organic synthesis as well. Probably Whitesides is afraid that KCN and/or Baran would recieve the Nobel prior to him receiving one!

    1. tt says:

      There is absolutely no possible way anyone doing total synthesis today should (or will) get a chemistry Nobel Prize. Just making molecules is not ground breaking science, no matter how elegant, efficient or clever the route. Discovering fundamentally new reactions with broad application, or pioneering a complete disruption in total synthesis is Nobel worthy.

    2. Potassium Cyanide will not... says:

      …have a Nobel price, neither Baran. Whitesides doesn’t have a shot either.

  18. Jacob says:

    I’m sort of amused (and saddened) by the amount of snide in Baran’s essay. Especially the sentence before ref. (11).

    The crux is, the second-last paragraph of his assay probably won’t be the best way to convince effectively high school students or college freshmen to devote themselves to the great endeavor of natural product total synthesis. Anyone who appreciates his essay and “the intricacies of the field” is most likely already in the field — even Whitesides is disqualified for that according to Baran. It seems to me that an essay of this sort is merely a display of power rather than an honest effort to persuade anyone.

    A side note, a few years ago at my alma mater (a well-regarded non-US univ with a pretty good chem department), the chemistry undergrads undertook sort of an anti-organic revolt that forced the dean to add more math/physical/computation stuff to their previously organic-centered curriculum. The dean had to oblige because the chem department was bleeding undergrads (even those with high GPA in chemistry) through declining number of high-school applicants, freshmen and sophomores changing to other majors, and seniors refusing to apply for PhD programs in chemistry.

  19. Sebastien says:

    I am not entirely sure that Kuhn had fields like organic chemistry in mind when he developed his paradigm theory. Perhaps the question that organic synthesis raises is that of what occurs when and if a branch of science turns into a type of engineering/technology. It would seem to me that modern organic synthesis, in its purest form, is now very different from fields that still ask questions related to how nature works.

    1. milkshake says:

      Organic synthesis is in fact a form of engineering done with the help of chemicals. It is progressively harder to find a fundamentally new reaction like metathesis and photoredox catalysis. Baran’s group approach – taking hard problems and finding new synthetic solutions for them – is the way synthetic chemistry should be done but it is not easily replicable since the progress depends not just on smart motivated people full of research idea but rather on the body of work that needs to be funded long before there is anything useful in sight. In the end, the labs that excel do not necessarily have the most brilliant PI, they first need to be good managers and charismatic leaders. But the system of grant funding and tenure track creates its own perverse incentives so thats why there is so much shaff nowadays.

  20. AVS-600 says:

    “total synthesis trains students well, industry likes to hire people who do it,”

    If this is the most important justification for the existence of total synthesis groups, the awkward follow-up question should probably be “why do we want the government to give these companies’ future employees free training in a field that’s already overcrowded with candidates?”

  21. Me says:

    Wow long comments list.

    This discussion does remind me of some experiences I had in my decade-long tenure as a med chemist, like why we paid external consultants 10’s of 1000’s of $$$ to come in and try to re-work all of our syntheses so that they contained their favorite reaction rather than troubleshoot our genuine problems (Baran actually was a pretty decent exception to this).
    I always wondered why, after a while, I stopped leaving the MEDI hall at ACS meetings and often wondered if there was too much vanity in academic circles.

  22. Matthew says:

    Automation and other high-throughput chemistry technologies have more than demonstrated their efficacy in identifying new areas of reaction space, solving complex synthetic problems, and increasing the overall throughput / efficiency of synthesis. While material constraints and specialized equipment preclude many chemists from leveraging these approaches, the technologies are now present in many North American industrial and academic institutions. We are now starting to see the convergence of these technologies with machine / deep learning tools, which will open up new avenues of organic chemistry.
    Societal need will ultimately determine where applied organic chemistry will focus and this will, in turn, drive funding cycles in both business and academia. Overall, no need to panic – we are far from being a mature field, at least judging by some of the comments… 🙂

  23. Janice says:

    Phil Baran is a funny guy. He comes off as this super public figure/servant, and yet i was a grad student at tsri for 5 years, published a nature paper, and the dude never even talked to me once. I interacted with him once and he passive aggressively handed me one of his handouts, probably to teach me one of the many lessons he thought grad students needed. That is fairly typical of the culture there. Assume the worst in students.

  24. Anon says:

    I agree that it’s great training. However, I do not agree with the notion that the pharmaceutical industry likes to recruit people who did total synthesis for their PhD. I completed a PhD in total synthesis that was successful and we published our work around 4 years ago in a very good journal. I’ve found it very difficult to obtain a job in pharma as a medicinal chemist (I’m still trying). Every job I see advertised asks for experience, and even if it doesn’t the job market is saturated, so chances are someone with experience will get it. Perhaps things are different in the US?

  25. Rochewise says:

    No pain, no gain! Total synthesis is by far better than methodology for acquiring broad knowledge of organic chemistry. Even the best recent methodology-only PhDs seem incapable of solving fairly simple organic chemistry problems. This is why Pharma, Agro etc favor those trained in TS.

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