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The End of Synthesis

“It’s not the end of the earth. But you can see it from there.” That was Lou Holtz, talking about coaching football in Fayetteville, Arkansas. But today I’m talking about a new paper from Marty Burke and his group at Illinois, and although it isn’t the end of organic synthesis, you can see it from there.
Now, that sounds a bit frightening, or a bit idiotic, or maybe a bit of both. But have a look at the paper. I had a chance to see him talk about this work a few months ago – I found it fascinating and startling, and I’ve been thinking about the implications ever since. This paper is the perfect opportunity to talk about it all (here’s a commentary at Science). It’s a summary of a lot of work that the Burke lab has been publishing over the last few years, and when you put it all together, there are some far-reaching consequences. On one level, it’s about assembling sets of molecules from modular building blocks, each containing MIDA boronates and bromides. That’s been a worthwhile reaction to study, since these boronates are very easy to handle and shelf-stable. What Burke’s group has found, though, is that the MIDA complexes have an unusual property: they stick to silica, even when eluted with MeOH/ether. But THF moves them right off.
MIDA scheme
This trick allows something very useful indeed. It’s a universal catch-and-release for organic intermediates. And that, as the paper shows, opens the door to a lot of automated synthesis. You take a MIDA boronate intermediate, and deprotect it to the free boronic acid. You then couple it to another intermediate, which has a reactive bromide (or what have you) at one end, and another MIDA boronate at the other. The solvent switch lets you purify the crude reaction by loading it onto silica, washing everything else off with MeOH/ether, and then eluting the MIDA-containing product with THF. Then you do it again. And again.
The paper shows a wide range of products produced in just this fashion. Yields are decent, although varied, but there’s always product coming out the other end at some level. The number of possible compounds that can be made in this way is limited, at the first level, by the number of MIDA-boronate containing intermediates that you can synthesize, and you can certainly make a heap. At the second level, it’s limited by the sorts of couplings that boronic acids can do, and we still don’t have general methods to make them do bond formation between saturated carbons very well. But that’s an area of intensive research, and it looks like a solvable problem, eventually. I would go so far as to suggest that this paper makes a good case for trying to get this to work with boronic acids (as opposed to alkylboranes, etc.), because of the immediate application of the catch-and-release purification, but we’ll see what happens.
What gets me about this current paper, though, is the concept behind it. This has the potential to take a large part of organic synthesis into the realm now occupied by peptide and nucleotide synthesis. Those two are certainly easier problems – you have one kind of bond between every subunit, and a limited number of subunits themselves. But the advent of solid-phase iterative methods to synthesize these sorts of molecules was still a huge advance. It took making such things out of the realm of every-one-a-new-individual-challenge, and into the world of “Sure, we should be able to make that. Fire up the machine.”
That first category, we should note, is where total synthesis of natural products has traditionally been. And proudly so. I’ve had a lot to say about that over the years around here, going back to 2002, but I’ll summarize: I think that total synthesis was, at one time, one of the most vital and important parts of organic chemistry. But that day is past. Modern analytical methods have largely (although not quite totally) eroded the structure determination reasons for doing it, and modern synthetic techniques have put a vast number of molecules within theoretical reach. “Theoretical”, in this case, meaning “Given enough postdocs, enough grant money, and enough time”. That certainly wasn’t always the case. When Woodward, Stork, or (fill in your favorite here) started out to synthesize some complex molecule back fifty years ago, it was often not very clear at all how one might go about it. Just coming up with a semi-plausible synthetic route was a real intellectual accomplishment, and dealing with what happened when these ideas met the real world was another. Total synthesis took all the brainpower and all the skill that could be brought to bear on it.
It’s still not easy. But it’s sure not the same. It’s much harder to draw a molecule that’s truly a stumper these days. We have so many reactions and approaches that you can generally come up with at least a paper synthesis – mind you, it may not be a very nice paper synthesis, but in the old days you probably couldn’t even come up with that much. So if fewer and fewer molecules really are an adventure – or really promise to advance human knowledge in the course of making them – what’s left?
What’s left, I’d say, is for organic synthesis to get braced to take the next step. That is, it needs to stop being an end in itself, and start becoming a means to other ends. That’s already what we use it for in drug research – the only reason we do organic chemistry is that we don’t know any other ways to make small-molecule drug candidates. In the earlier stages of a project, we don’t much care about way we make things, just so long as they get made. As I’m fond of saying, in discovery med-chem, there are only two yields: enough and not enough. Did you make a sample of the compound that can be tested in the assay? That’s enough. And that’s the primary concern – how you made it is secondary. This is sometimes a bit of a surprise for people coming from high-powered academic synthesis groups, because you can do an awful lot of good med-chem using just reactions from the first semester of sophomore organic chemistry, and you can do an awful lot of good med-chem while putting up with reaction yields that no academic group would stand for. But one adjusts.
We may all need to adjust. What if this MIDA boronate protocol, or some later variant of it, starts turning big swaths of organic synthesis into a process of stick-the-pieces-together? Like peptide synthesis? These routes may not be the most elegant and highest-yielding things ever seen, especially not at first. But that leads to the question of why you’re making these molecules in the first place. Are you making them so that you can do something with them – test them as drugs, use them as nanotech building blocks, make a new battery or solar cell, investigate a new kind of material? Then fine – you probably have enough now to get started on the next phase of that idea, thanks to this Synth-O-Matic over here. Or are you trying to make the best possible synthesis of your molecules (fewest steps, highest yield, etc.)? In that case, you need to be careful. That’s a very worthy goal if you already know that this is a valuable molecule, which is what the process chemists do in industry. But if it’s just another new molecule, then why are you optimizing its synthesis? If along the way you’re discovering new and better synthetic reactions and protocols, then good for you – but I would define “better” as “better able to be used to crank out new molecules for other purposes”, not “done in five fewer steps than the last group had to use to make the same molecule”. Not that alone. Not any more.
If organic synthesis become modular, then the new chemistry and new reactions are going to go more into making new modules. All our problems are still there – tricky functionality, multiple chiral centers, quaternary carbons. But if we end up making large molecules mostly by looking for boronate disconnections and stitching the pieces together, then we’re on a hunt to make the pieces, not to make the whole molecules.
But what about the art? What about the elegance? Well, we’re going to have to say goodbye to some of it. The printing press drove fine hand copy from the world – you don’t see so many gold-leaf illuminated letters any more. More recently, and in our own field, the advent of modern analytical chemistry drove out the classic methods of structure determination. Now there was a puzzle worthy of the finest thinking that could be thrown at it. Old-fashioned degradation and derivatization was a fiendishly difficult challenge, like playing chess with the lights off and the moves called out in a language you don’t know. But that kind of chemistry is gone, totally gone, and it’ll never come back. No one does it like that any more. There were chemists who just couldn’t face that, when it happened back in the 1960s and into the 1970s, when they found that what they were really good at was no longer of value. It was hard. But organic synthesis may have to face up to the same sort of realization, that time has overtaken it and that arts gratia artis is no longer a fit slogan to work by. This paper today is the first one that’s really made me think that this transition is in sight. For me, organic synthesis is never quite going to be the same.
But in science, when something dies it’s because something else is being born. The idea, the hope, is that if the field does become modular and mechanized, that it frees us up to do things that we couldn’t do before. Think about biomolecules: if peptides and oligonucleotides still had to be synthesized as if they were huge natural products, by human-wave-attack teams of day-and-night grad students, how far do you think biology would have gotten by now? Synthesizing such things was Nobel-worthy at first, then worth a PhD all by themselves, but now it’s a routine part of everyday work. Organic synthesis is heading down the exact same road – more slowly, because it’a a much harder problem, but (I think inexorably). Get ready for it. We’re going to need to stop being so focused on just making molecules, and start to think more about what we do with them.
Note: for previous (and partly superseded) thoughts here on automated organic synthesis, see this post.
Update: for more thoughts on this, see here.

73 comments on “The End of Synthesis”

  1. Anonymous says:

    Striking article, Derek. With the advent of computational modeling I think we are starting to see the “new wave” in other areas of biology and medicine as well. Predictable enzyme function, protein folding, so on and so forth.
    Add in modular semi-automated synthetic chemistry and I think we are starting to see the shape of the future for much of the ‘routine’ research currently being performed.

  2. Wavefunction says:

    Looks like a pretty neat paper. You are echoing something that George Whitesides has often said (which I blogged about – linked in my handle): Chemists need to move beyond the molecule. Organic synthesis has become commoditized and is no longer the creative frontier in chemistry. Chemists need to find new pastures to fertilize if they want to truly push the boundaries of their science.
    But in some sense synthesis should be proud of itself for getting to this state of affairs, since this is what happens when a science becomes a victim of its own success, when its vital processes become so fine-honed and standardized that an undergraduate (or a chemist in China or India) can do them in an afternoon. So let’s wear that badge with honor and move on to the next battlefield.

  3. Justin says:

    Well done, Derek, and kudos to Burke et al.
    Regarding the art, it’ll still be there. Somewhere.
    “There is no science without fancy and no art without fact” -Nabokov

  4. Hap says:

    This seems nice, but it seems sort of early to pull the sheet over synthesis. It’s good to have robust modular techniques where you can use them, and the functionality (aryl/alkenyl groups) that Burke’s group is developing methods for using is modular, but most targets aren’t likely to fit that methodology. Instead, lots of targets have lots of interacting groups or don’t have obvious substructures that can be assembled in such a manner. This would help with lots of things (and maybe lots of what med chemists make) but not with lots of other things.
    Also, lots of peptide couplings (trying to make macrocyclic peptides or peptide lactones, particularly hindered ones) don’t work all that well – they require lots of tinkering to work. This after lots of time and uncounted papers on the topic.
    As a side note, the concept of synthesis being described by standard methods in papers is a little frightening. Having seen peptide papers, the lack of explicitness in that mode of description (“no I don’t actually want to write an experimental section.”) is not helpful. Also,”Standards are great. There are so many to choose from.”

  5. Horacio Gomez says:

    Truly amazing that so many can be fooled by this – surprised that even you, Derek, would take the bait.
    This paper will do far more harm than good because ignorant biologists and non-chemists will think that what we do can be automated now. In reality there is so much that organic synthesis cannot do and this paper takes attention away from that simple fact. All this is, is a faster way to make a small subsection of things we can already make. There’s no real advantage to this over Solid phase synthesis with a regular linked small molecule. That can be automated too.
    Sure, this is the end of synthesis if we as a community are done innovating.

  6. a. nonymaus says:

    The end of synthesis? No.
    The end of chromatography? Perhaps for a subset of syntheses.
    It will open up a whole new world of synthetic routes to the bifunctional boronate precursors, though.

  7. Chemjobber says:

    Linked in my handle is the HHMI press release, including quotes from Professor Burke:
    Ultimately, Burke says, he is excited about the opportunity to empower non-specialists – all kinds of scientists, engineers, medical doctors, and even the public – to produce small molecules. “When you put the power to manufacture into the hands of everyone, history speaks toward tremendous impact,” he says. “A 3D printer for molecules could allow us to harness all the creativity, innovation, and outside-the-box thinking that comes when non-experts start to use technology that used to only be in the hands of a select few.”

  8. milkshake says:

    this will be useful for analoging lead compounds in parallel synthesis fashion, but seriously – the end of synthesis? Please don’t let the management folks learn about this, they already believe chemistry R&D is too easy, too expensive and always past the deadline…

  9. Anonymous says:

    If you set up these automated reactions we’ll lay you off with a fat benefits package, if you don’t, well, we’ll just lay you off…

  10. Lyle Langley says:

    As feared, a lot of looking around the tunnels of Chicago and only coming up with an empty bottle. Well done Geraldo! This is what was necessary to have a blank post to trumpet? Was there a prize for the most clicks at 2 pm? And to quote Lisa and Bart Simpson, meh. M-E-H, Meh.

  11. Anonymous says:

    So if this is the end of synthesis, where do we get all the fancy building blocks?

  12. watcher says:

    There will still be new chemistry and related tricks developed…but the days when making complicated molecules was considered “art” might be in the past.
    Cycles come and cycles go.
    Ce La Vie.

  13. Ann O Mouse says:

    I am trying to understand why this article and this science, as interesting as it is, was worthy of a “breaking news at 2PM” alert on In The Pipeline, something that I think is unprecedented. I also am curious what PR firm Professor Burke hired to promote his work and why his financial interest (company has been started based on his work) is not mentioned. It is interesting work and has some important implications, but jeeze, hyperbole much?

  14. Ricard Rich says:

    Wow imagine if Corey hyped the TBS protecting group as much as this guy is promoting a protecting group for a boronic acid.
    Good grief. Wake up folks..

  15. Farmhand says:

    @2-Wavefunction
    “Chemists need to find new pastures to fertilize if they want to truly push the boundaries of their science.”
    I want to believe that you are not saying that chemists need to find a new place to crap. I have always thought that what we did was so much more than that, that we find fertile ground for our seeds to bear fruit, not just spread manure so someone else can make something grow. Maybe I am wrong.

  16. JFlavius says:

    Wow, a lot of hate for this work here in the comments. I agree with Derek’s perspective though and it makes me (an organic chemistry PhD candidate) sad and kind of worried. Sad that this field that I love might one day be thought of the way I think about peptide coupling chemistry (Ech!). Worried that my job prospects might be highly limited in 20 years time.
    This is clearly very good work and I think people need to understand that this is not the final product, but rather a proof of concept that, for the first time, shows that fully automated synthesis is entirely possible. Yes, the process is limited to sp2-sp2 (and primary sp3) coupling at the moment and we haven’t yet made an infinite catalog of BMIDA compounds, but these are only challenges that will eventually be overcome. The battle has only just begun, but it has already been won. Cheers to Burke and his students though, truly fantastic work.

  17. Ann O Mouse says:

    @18
    No hate for the work (it’s great), just extreme disappointment at the shameless and hyperbole-filled promotion for a commercial enterprise.

  18. JohnHunt says:

    If this is able to build molecules which have no natural process of being made then scientists might be randomly or systematically poking around in novel chemical space and accidentally produce a chemical ecophage which, for example, would consume all atmospheric CO2 until completion thereby potentially explaining Fermi’s Paradox.

  19. road says:

    I agree with @14. How is this different from combichem? I’m not bashing this work (or combichem) but it seems like a new instance of a technique that’s been well-explored, and that didn’t deliver the revolutions it promised 2 decades ago…

  20. David Borhani says:

    Agreed that it is very pretty and probably useful work.
    But, I don’t quite understand the hyperbole, either from Derek (especially) or Prof. Burke. Derek: “This has the potential to take a large part of organic synthesis into the realm now occupied by peptide and nucleotide synthesis.”
    Really? By stringing together linear, combichem-like pieces more easily? We’ve been there, done that. Admittedly, if shrewdly chosen, those pieces can sometimes be cyclized or otherwise converted to more complicated, interesting molecules, such as the secodaphnane core, but then we’re back to either more traditional chemistry, or restricting ourselves to a rather limited target space.
    But maybe I just don’t “get” it…

  21. DN says:

    The cool part is that there will soon be a catalog of 100,000+ building blocks, and you can simply order any string of them from a website. The next morning FedEx brings them to you in a vial. And the building blocks will be fabulous: fluorophores, repetitive crystallizers, booby traps for metabolic pathways, pH sensitive tags, technitium binding sites, approved drugs, and many more. Some companies will even let you specify permutations of general properties. You won’t get a vial but a 5,000-well plate.

    It will make organic chem more like circuit boards. Only a moron breaks out the chemicals and photomasks and etches their own boards, not when you can buy them for $25 and get a little box of miracles in the mail in a day.

    P.S. This is the sort of thing Andy Grove was talking about. Put down the fucking flask and work smarter, not harder.

  22. Anonymous says:

    Have to agree with both #4 and #11. Interesting, but “Meh”
    The scope is limited for now, so forgive me if I don’t start packing up my desk quite yet.

  23. anonymous says:

    Burke has always been a shameless self promoter. Anyone whose worked with boronic acids no they stick to silica. The only cool thing is that Burke figured out a way to capitalize on it. Nevertheless,it’s a different turn on combichem/diversity oriented synthesis and the fools in management will eat it up.

  24. bad wolf says:

    This post is so overblown i almost suspect Derek of succumbing to sarcasm.
    I never understood Burke, since way back when he was mentioned in a C&EN article about MD/PhDs. Still, he had one of the most arrogant-looking pictures i ever saw in the article (linked in handle).

  25. MarkySparky says:

    I like the angle of democratizing synthesis, albeit for a limited range of compounds. There is a hell of a lot of basic work that can be done with this type of approach, even if it needs to be refined with *real* chemistry later on.

  26. luysii says:

    It’s a good thing RBW isn’t around to see this
    For details see — https://luysii.wordpress.com/2011/03/01/what-would-woodward-say/

  27. David Borhani says:

    Anybody understand the 1.5% MeOH/Et2O does not elute, THF does elute behavior of MIDA boronates, and care to enlighten this aging chemist? Seems a bit odd.
    Also, if ALL the MIDA boronates stick, and are then eluted, won’t any unreacted MIDA boronate carry on to the next reaction? Asked another way, how does one ensure that all the MIDA boronate is consumed in the first reaction? (In nucleotide synthesis, it is by vast excess of one reagent, if I recall correctly.)

  28. JustAnotherGradStudent says:

    #28 – The MIDA boronates themselves are unreactive. However, they are readily cleaved to the corresponding boronic acids under mild aqueous basic conditions. In The Machine, the MIDA boronate is dissolved up in water with NaOH, hydrolyses, and is then subjected to the cross-coupling.
    I guess that means the reactive species (boronic acid) will be eluted in the 1.5% MeOH/ether stage of purification. I suppose if the initial hydrolysis is not quantitative, then you could have that issue of remnant MIDA boronate in the following steps.
    Then again, that would only be an issue if you were making something novel. If you could use this process for automated synthesis of known compounds, the conditions could be optimised. The whole thing is essentially run by computer – just tell the computer what quantities/temperatures/reaction times are best for a particular known synthesis, and it can do the rest.

  29. JBstein says:

    When you listen to his talks Burke IS persuasive, but then reflecting on the real impact on small molecule SAR chemistry … doubt is getting the best of this concept. Peptides and nucleotides are made via one single connection from a rather limited number of building blocs. No way this approach will prove useful for the diversity of organic building blocks and bond types available to the organic chemist. Being mean: this is the defrosted version of “high throughput paralell synthesis” – anybody seen something useful coming out of that hype ever ?
    It’s nice work, no doubt – congrats to Burke, will chip the best out of nanomaterials and other dendirmers, but get your brains working again. There are receptors waiting for your molecules …

  30. researchfella says:

    Wow, interesting stuff, but let’s not get so excited. I was going to say a lot more, but others such as David Borhani (#22) have said exactly what I had in mind.
    Derek, you need to think about this some more, re-read some of the old ‘exciting’ articles on solid phase organic synthesis and consider what that revolution led us to, and then post your reassessment with an apology.

  31. Idi Amine says:

    I find this post very interesting. Yes, it is impressive technical work and yes, it could expand the scope of possible reactions, but I wonder what could have been responsible for an unprecedented “pre-post” which kept everyone waiting with bated breath and an actual post titled “The End of Synthesis”. I have always known Derek to be an extremely cautious and skeptical person so I am genuinely curious as to what he saw in this particular paper that sent him over the moon. This was very unlike him.

  32. Anonified says:

    Does anyone else realize you gotta use a $#!T ton of the first building block to make a few mg of product?

  33. David Borhani says:

    @30: thanks for clarifying. So if MIDA boronate hydrolysis is quantitative, which I presume could be easily forced to be true, then no “left side” reactant would remain (as drawn in the many schemes in the paper; “right side” reactant is a bromo-MIDA boronate, typically). But what if the coupling isn’t quantitative? Then “right side” bromo-MIDA boronate does remain, mixed in with product MIDA boronate. Both are captured on silica; both are eluted with THF.
    Or am I again missing something?
    @34: Thanks for the deja vu 😉 Worth noting, of course, that the best parts of all these kinds of semi-automated synthesis that have been developed and promoted (as THE answer) over the past few decades have been thoroughly adopted by Pharma and many academic labs. Think 24/48/96-vial focused libraries, mass-detected purification, etc.

  34. Anonymous says:

    Biologists have a lot more to worry about with automation than chemists. I’m currently in a grad program right now for biomedical engineering; pharma biologists in the next 20-30 years are going to have no idea what hit them once microfluidic platforms really start taking hold. We’re talking about screening 1 million compounds against a target in a matter of hours or less than a few days. Gone are the days for rooms full of compounds and big machines needed for HTS. Gone will be the scientists needed to run PCR, western blots, or virtually any other assay. Customizable microfluidics is going to layoff 80% of people on the biology side.

  35. Anonymous says:

    wow … another wat to make sp2-sp2 bonds – wasn’t the noble already given for this? hasn’t there been a bunch of papers saying the success of this chemistry resulted in the uniformity of leads?

  36. Nick K says:

    The End of Synthesis? Really? All I see are flat, linear oligomers of aromatics and heteroaromatics, all easily accessible by straightforward Suzuki chemistry. What about the third dimension? What about asymmetric centres? What about saturated rings?

  37. anon says:

    @25
    from his CV (available on his webpage)

    Fall 2008
    “Teacher Ranked as Excellent” and “Teacher Ranked as Outstanding”
    Spring 2007
    Chemistry 237: “Structure and Synthesis”
    “Teacher Ranked
    as Excellent””

  38. Anonymouse says:

    @26, bad wolf.
    Derek, I get it, you reviewed the paper! But why didn’t Science ask you to write a Perspectives piece on it? Too many chemistry articles in this issue of Science? Or they wanted to do that big PR “News” feature?
    Perhaps a Nature News & Views from you is forthcoming?

  39. Anonymous says:

    Hey now any Jesse Pinkman can be Walter White, no PhD required. Just type in the building blocks and out comes all the bioactive product your colorful friends can move. That is chemistry for the everyman.
    Back in the 80s Still said organic synthesis was no longer of consequence after the palytoxin synthesis. It was going to be much more about what to make moving into the future. However no one noticed that memo 20 years ago.

  40. Rhenium says:

    @26. You are correct, my back hand is itching. 😉

  41. Lyle Langley says:

    Third Rock Ventures launched Revolution Medicines with $45M in Series A. Pretty sure it’s not the “End of Synthesis” (sorry Dr. Lowe, but this was a big swing-and-mis), but Burke’s got some heavyweights drinking the kool-aid. No therapeutic area or novel compounds…but they have $$.

  42. T G says:

    Anonymous @37 Email me at toddgrahamny@yahoo.com. I’d love to talk to you for a bit.

  43. Anonymous says:

    @39
    I think if you mix this sort of platform with some of varinder aggerwal’s recent lithiation-borylation type chemistry to create polyketide-like structures, you are on to something really powerful.

  44. I think most of you are misreading Derek’s post.
    It’s not that this specific paper is It. It’s that this specific paper is arguably the tipping point, the point at which the ideas and methods began to cascade, to come fast and furious. This next decade could be the decade in which great swathes of synthesis fell to automated methods.
    Derek is saying that he is now convinced that it’s going to happen. Not that this scientist, that this group, this paper, has done it or will do it. Only that this paper is a harbinger. It will happen. And sooner than you think.

  45. Anonymous says:

    @44
    I work in natural product enzymology. Sometimes whole huge syntheses–most of some students’ PhDs–are dedicated to just making the substrate to explore some mechanistic enzymology (for example a late stage intermediate in a polyketide pathway). A company like Revolution medicines if they are doing the sort of chemistry described in this paper would open up a lot of freedom in my field to explore interesting chemistry.
    I’m sure there are many other fields where the molecule is a means to an end. If they can make molecules cheaply enough and they can be ordered the way you order an oligo for a PCR reaction, then that is really going to change a lot of areas of science and be quite lucrative. Although finding drugs would be great, there are certainly other applications.

  46. David Borhani says:

    @39, Nick K. See my comment, @22. Some 3D molecules *will* be accessible via a very carefully chosen arrangement of double bonds & functional groups. These tandem cyclization reactions were first demonstrated (IIRC) by Bill Johnson (R.I.P.) at Stanford. Heady stuff at the time, and even now! See: Johnson et al. “A new approach to steroid total synthesis. A nonenzymic biogenetic-like olefinic cyclization involving the stereospecific formation of five asymmetric centers.” JACS [1968] 90:2994. This work presaged the identification of such oriented cyclizationa that underly most enzymatic biosyntheses of terpenes, and di- & sesquiterpenes (cf. beautiful work of Joe Noel @ Salk, David Cane @ Brown, and others).
    But, I agree with your overall sentiment.

  47. Lyle Langley says:

    @48, Anonymous…
    I don’t disagree that other areas of science could be lucrative. They appear to be going after finding drugs. From the website…
    “REVOLUTION Medicines is an innovative and dynamic organization of expert biologists, chemists, pharmacologists, clinical scientists and business executives working together to discover and develop exciting new medicines from natural products.”

  48. eyesoars says:

    Andrew Molitor @47
    I have to agree with you. The comments here read like Derek just pooped in the punch bowl, and must be responding to a paper other than the one he’s citing.
    It’s not the end, or even the beginning of the end, but maybe the beginning of the end can be seen from here. And even “the end” will leave room for new chemistry and techniques for those things that can’t be done with this particular set of techniques.
    Certainly there will be such things, no matter how successful this technique is (complex organoborane syntheses?). But these general/generalizable techniques can only get better.

  49. Nick K says:

    #49 David Borhani: No dispute there, Johnson’s polyolefin cascade is one of the triumphs of Chemistry in the last century. However, I can’t see how that sort of synthesis could be automated. It’s also worth pointing out that it took Johnson and his group years of work before the yields were decent.

  50. Anonymous says:

    @14 The PR company is the corresponding author. Seriously, this is how he talks.

  51. BILLY says:

    Could the MIDA boronate functionality be added to traditional phenyl/benzyl protecting groups for other types of reactions in order to allow purification of those types of reactions?
    Is that kind of a logical next step, or am I reaching too much?
    E.g. TBDPS, or some silyl ether with a phenyl group? PMB? benzoyl?

  52. BILLY says:

    Could the MIDA boronate functionality be added to traditional phenyl/benzyl protecting groups for other types of reactions in order to allow purification of those types of reactions?
    Is that kind of a logical next step, or am I reaching too much?
    E.g. TBDPS, or some silyl ether with a phenyl group? PMB? benzoyl?

  53. BILLY says:

    Oops, meant phenyl/benzyl-containing. Although I’m not actually a synthetic chemist, so I might be completely off base. But presumably there are some phenyl/benzyl containing protecting groups that have good cleavage yields?

  54. Jay Bradner says:

    I have been following Marty’s work closely and with admiration. He is a true innovator, and friend. IMHO synthetic chemistry has been accessible to “medical doctors” for some time now…but that is speaking only as a medical doctor. As a side note medicine has faced the same speculative automation from the computer science field for years. Will big data and machine learning render diagnostic medicine obsolete? Both fields are safe, albeit under like pressure to reinvent themselves as more innovative, cost-effective, and beholden to health-related outcomes.

  55. Walter Model says:

    @BILLY (@54)
    exactly what I was thinking. I don’t really care for the automation and I don’t think it will have tot. syn. killing effect derek is gunning for but maybe it will help tot. syn. along by adding a “purification group” to our toolbox.

  56. Anonymous BMS Researcher says:

    “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”
    Winston Churchill
    I do not feel qualified to form an opinion of this specific paper, but I have known Derek for many years and if he thinks a paper important then I am inclined to think there may be something it it. Derek has been around the block a few times, and always calls it like he sees it.

  57. BH says:

    THANK YOU #9 & 22. ‘End of synthesis?’ Bullshit.

  58. David Borhani says:

    @52, Nick. Yes, agreed that crafting the polyolefin cyclization to give decent yields of the desired product is non-trivial. That was my point in my first comment, that some such products are going to be accessible, but the generality for producing complex products — in automated fashion — is unclear to me.

  59. Anonymous says:

    I can only imagine Derek succumbed to the gravitational pull exerted by Burke’s ego when he recently visited the University of Illinois. And probably has been mulling over this paper since then. Anyone who has ever met Marty knows he is a shameless self promoter.

  60. entropyGain says:

    I have yet to read the paper carefully, but the comments sure remind me of the solution phase vs solid phase debate around peptide synthesis way back when. When solid phase oligonucleotide synthesis came around it wasn’t very controversial, biology labs just bought a machine and made oligos. Now you get online, paste a 1000 bp sequence into a web page and for $100 get your synthetic gene sent in a few days.
    Personally, I find it refreshing to see an experience med chemist/blogger this excited about something new.

  61. Polymer bound says:

    This methodology seems like a cheaper version of the fluorous-phase catch and release stuff that the Curran group developed. Cool, but I don’t think you could argue that this is even a blueprint for the end of synthesis, as much as I’d like that day to come. Working with chemicals sucks.

  62. Inorganoman says:

    The end of synthesis? What a horrible title. Carbon is one element on the periodic table, and just because its chemistry can be automated poorly this represents the start of the end of synthesis as a whole?
    What about the synthetic chemistry of phosphorus? Germanium? Tin? The transition metals? Inorganic synthesis is still in its infancy and there is so much happening right now that to say “The end of synthesis” not only represents a severe lack of knowledge, but also suggests to the greater scientific community that all synthetic chemists will be at risk, when chances are this is FAR from the truth.

  63. Anonymous says:

    woo, Jesse Pinkman may dump Walter White in 3 episodes.

  64. science says:

    I don’t think this paper is “Science” worthy.

  65. MoMo says:

    Amphotericin analogs are even needed in medicine?
    Who knew?
    ZZZZZZ!ZZZZZZZZZZZZZZZZZZZZZZZZZZZZ!

  66. Anonymous says:

    /i>

  67. cookingwithsolvents says:

    Billy above may be cited as the first time a blog post made a ‘common knowledge’ contribution in IP space in chemistry if they didn’t file their IP right. 🙂

  68. Pingback: In the Pipeline

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