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Boring! Or: The Medicinal Chemist’s Toolkit

There’s a new paper out on a topic that is of great interest for medicinal chemists: what sort of chemistry is it that we’re spending all our time doing? It’s a study of the literature from 1984 to 2014, analyzed by reaction type and other factors, and here’s the take-home: “. . .of the current most frequently used synthetic reactions, none were discovered within the last twenty years, and only two in the 1980’s and 1990’s. . .” Those two, as you have probably already guessed, are palladium-catalyzed couplings (Suzuki-Miyaura and Buchwald-Hartwig). (Here are some other analyses like this from the last few years, for comparison – that last one is a fifty-year retrospective, for example).

Here’s a post on this latest paper from Wavefunction, who calls the conclusions of the paper both depressing and embarrassing. I’m trying to decide if I agree with that. Overall, I would expect any such analysis (a wide number of choices over time between a large number of alternatives) to show power-law behavior, with a relatively small number of reactions dominating the list and a long tail of others stretching out behind them, and that’s pretty much what we have. So I’m not amazed at all that twenty or so reactions make the up the bulk of the med-chem literature – I’d be amazed if that weren’t the case. Best-seller lists are a good analogy; the great bulk of the sales are in the top ranks of any such list, and I’d expect a roundup of the biggest-selling books of the last thirty years to show a roughly similar distribution.

One difference, though, is that fashions in books can change more quickly and more easily than do favorite chemical reactions. Don’t tell an unpublished author this, but the barriers to entry are lower. And while there are infinitely many ways to write a novel, every single amide-bond-forming reaction makes an amide, and no one’s going to discover a newer and more fashionable amide compound class. That limitation on the number of bonding patterns in organic chemistry will emphasize the power-law aspects of such reaction counts even more.

What we do have, though, are occasional ways in which existing bonding arrangements suddenly become easier to realize, and there you have the palladium-catalyzed couplings. If further work in the field eventually brings us to efficient, reliable C-C bond formation between plain sp3 carbons especially chiral ones, which I will deem provisionally the “zambodium-catalyzed alkyl coupling reaction”, then you can expect it to shoot to the top of the charts as well, since such bonds are the basic currency of all organic chemistry. No one would find it depressing or embarrassing that the good ol’ ZCAC reaction was being used all over the place – it would have to be used all over the place. You’d have to be an eccentric weirdo and deliberately trying to avoid it.

Now, the current metal-catalyzed coupling reactions are not quite in that class, of course. And I don’t think that anyone doubts that there’s been a proliferation of aryl-(hetero)aryl bond formation since the early 1990s in medicinal chemistry. It’s a combination of several factors. First off, such bond formations were not easy to do before palladium-catalyzed coupling, and in fact, they seemed rather magical once they began to become popular. Second, they’re experimentally fairly easy – sure, optimizing them can certainly be a chore, but you can usually slap a coupling reaction together under pretty standard conditions and expect some sort of product to come out the other end in most cases. And third, the reaction produces structures that are pharmacologically favorable. Biphenyl-type structures were already known as pharmacophores before the Suzuki reaction made them easier to get to, and the general hinge-binding behavior of kinase inhibitors matched up well with both it and the aryl-amine couplings (those two, the target space and the reactions, helped make each other popular).

More on that second point, which is an overall influence on any such list of popular reactions. Remember, in medicinal chemistry, we spend a lot of time analoging, fruitlessly, into the void. This means that there is no way that a reaction can become a top-twenty favorite without being experimentally easy and adaptable to a wide range of substrates. That’s the very definition of one; no one should be surprised to see them there. What’s worth asking, though, is how the compounds we make are being determined by what reactions we find most easy and versatile, and whether this compound set is a decent fit for what we actually need to have to prosecute our med-chem targets.

There’s where the objections come in to all those Suzukis. You cannot, I feel sure, make your way forever into target space by stringing aryl groups together like links of sausages, but that’s what the reaction does, and its products are a larger proportion of the available compounds than they probably should be. Similarly, I don’t think that a library of every available aryl carboxylic acid condensed with every available aniline is going to be the answer to all questions, either (but as the example of DNA-encoded libraries shows us, if you have access to such a set, you might as well screen it!) So what kinds of compounds do you need to address the wide world of targets, and what kinds of reactions are needed to produce them?

This new paper makes a comparison to natural products, and that’s probably as good a way to look at the problem as any. Evolution has been exploring target space for a long time, with a range of chemistries at its disposal (although certainly with its own limitations as to reagents and conditions, a fact that’s not always appreciated). As this analysis shows, the sorts of products we make in med-chem aren’t a very good fit into the natural products universe, and similarly, the sorts of reactions we use to make them aren’t, either. One result might be to call for medicinal chemists to try to deliberately run more varied reactions, and I can endorse that. There certainly are reactions that are under-used, and when a new transformation shows up in the literature, its incumbent on medicinal chemists to give it a try and see how well it works. But remember, as long as “more varied” means “harder to run and less general”, that call is not going to get as far as you’d like. So another call would be for efforts to make natural-product-like space more chemically accessible: we need more robust reactions to get there.

And while we’re thinking about natural products, remember that the term usually refers to the more exotic substances that organisms produce. But if you look at the whole universe of biomolecules, then it starts to look just as boring and stuck-in-a-rut as medicinal chemistry. Sure, we use amide couplings a lot – but not as much as ribosomes do (and with only twenty amino acids, too). Amides, carboxylate esters, glycosides, phosphate esters – the great huge bulk of the chemistry of life involves manipulating just those linkages and a few others, over and over and over. It manages not be boring.



27 comments on “Boring! Or: The Medicinal Chemist’s Toolkit”

  1. Ash (Wavefunction) says:

    Thanks for the plug Derek. I would call the conclusions of the paper depressing, embarrassing and promising (in terms of new reactions that can be explored). One thing which others pointed out is how much of this quantity vs quality tussle is driven by upper management who are interested in compound number more than kind.

  2. TFN says:

    Great post Derek. A call to action for developing the ZCAC reaction indeed!
    I’d also like to add to the discussion that there is another under-utilized approach for accessing sp3-rich analogs for drug discovery programs: semi-synthesis. With all of the recent advances in bioengineering which are now able to produce complex natural products on large scale, semi-synthetic derivitization of those NPs could provide a hybrid solution of making molecules with plenty of three-dimensional structure (brought to you by nature) and analog-ability (brought you by Suzuki and friends).

  3. And thanks to you for the plug Ash. You summarized it well. There’s indeed a high bar of impact for new synthetic reactions in drug discovery. As you say, one reason for this is the metrics era and pressure on delivery from mgnt, and chemists (quite possibly as a result) taking the easy way out making compounds “just because they can”, There are many other reasons as well (the paper is 16 pages ; ). One thing I’d think most can agree on is the recommendations we make “to educate medicinal chemists who are new to the field to have a strong rationale behind (almost) all designed compounds and selecting the most appropriate routes not the most expedient routes”?

  4. Anon says:

    I’d love to see a list of these under-utilized reactions.

  5. Dean Brown says:

    I like the post by TFN around the potential of semi-synthesis. I think this also encompasses ideas like directed evolution with novel feedstocks as well as discrete biocatalytic methods to expand our chemical universe. There is some interesting science coming along in those areas, but it seems like it mostly sits within biology/chemical biology labs perhaps looking for an application.

    As an FYI, I joined the industry at a time in the late 1990’s where I caught the tail-end of the era where we made small numbers of compounds in large amounts because in vivo screening was maybe the second or third assay in the cascade. That changed quickly. I distinctly remember the first conversation I had with a senior chemistry leader who claimed we weren’t making enough compounds (~1998?). Luckily it was a minority view at the time, but nonetheless makes a lasting unfavorable impression on a young medicinal chemist. There also has been another interesting cultural change in my view. Many of us were trained in an environment where the medicinal chemist was expected to be a renaissance scientist and become an expert in every other enabling field ouside of synthetic chemistry. Perhaps this led to a high chemo-centric focus at senior levels of management as chemists held quite a bit of influence on key decisions? For better or worse, the industry is changing, and as Ash quoted in his column “better to light a candle than curse the darkness”. As Derek points out about the analysis in the paper, the most frequent reactions come as no surprise and may show power-law behavior. But, there are exceptions to the analsyis for sure, and perhaps one worth looking at in detail. I know there are biotechs and large pharma alike who are pursuing complex scaffolds, where they have the confidence it is the right place to be (e.g. antibacterials and natural product sources). However, these seem to be in the minority.

    One final thought as well. I think we often employ a variety of diverse chemistry to acccess key building blocks, especially when it comes to optimizing those synthetic schemes. I think the issue is that we focus on a narrow set of final reactions to produce final compound with thoughts such as “I wonder if I could hang a carboxylic acid and make some amides, or a bromine and do some bi-aryl coupling”. Why don’t we think differently such as “maybe I can make a diene building block and make a Diels-Alder library? or an epoxide building block and open with nucelophiles?” It just doesn’t happen that often, probably because of complexities of stereochemistry, regiochemistry and stability of starting materials, etc.

    Anyways, those are my thoughts. Thanks for the debate.

  6. Phil says:

    I would be interested to see the results of a similar study in process chemistry. Since they have a little bit more time to explore options, I would suspect that process chemists can take chances on sexier chemistry that will require some optimization. I feel like there is more new chemistry in papers from process groups, but that may be the availability heuristic talking (I’m recalling specific examples of things like CH activation and hydrogen-borrowing in OPRD). On the other hand, old chemistry tends to work on scale, so it’s possible the fraction would be even smaller.

    Another point, using the reaction discovery date sets the bar really high. The Buchwald-Hartwig reaction was discovered in the 90’s, but the conditions people use regularly were developed in the mid-to-late 2000’s (BrettPhos, palladacycle precatalysts, etc). CH activation was discovered in the 90’s (or earlier), but the development of truly general rules and conditions is still ongoing. Chemistry in its freshly JACS/Science/Nature-published form is rarely practical, let alone useful.

    1. Chemjobber says:

      Linked in my handle is the latest OPRD (2015) ~survey of API manufacturing steps. Still pretty standard stuff. Interesting how the authors are surprised at the relatively high number of Suzukis, etc.

      1. Sfuns says:

        I’m a process chemist in agrochemical industry where scale of production is substantially larger than in Pharma and the final price is critical. Reactions we tend to use do differ somewhat from those used by our discovery colleagues. The best example I can think off is a complete absence of Suzuki couplings. Just too expensive and atom inefficient.

      2. Phil says:

        Thanks CJ. It’s going to take me some time to sift through that paper, but looking only at intermediates does have limitations. No surprise that amines and aldehydes are among the most common intermediates, but there are newer, more atom efficient ways to do reductive amination that I would say go in the “non-boring” column.

  7. Rule (of 5) Breaker says:

    I am with you Derek – we need more robust reactions. Too often, the reactions are very limited and specific or at best unproven in a wider range of substrates. One will see a paper titled “Blah, Blah…Couplings of Amines to Aryl Halides.” Then you read the paper to find out that what they really mean is only secondary amines to only iodophenyls (heterocycles don’t work) and only in toluene. If academics want to impress me, show me a reaction that works in the presence of many functional groups and in a solvent like DMF because many of the advanced compounds that I have worked with over my career have no solubility in toluene. OK, now I digress.

    Jonas, you have a point with appropriate vs. expedient. At the same time, we must consider a discovery chemist’s primary focus. As far as I am concerned that is speed. If a new reaction comes out, but I will likely have to “play with the conditions” to get it to work, then I’ll take a pass a lot of the time if I have an alternative route. My job is to make compounds that answer questions about the target as fast as possible. We are in a race against time: with other companies to be first, with patients to meet treatment needs, and with management before they think progress has been too slow and pull the plug on the project. Certainly for important scale-ups or chemistry we will need repeatedly, we will spend time optimizing. But most of the time, I will pick whatever route gets me there the fastest no matter how brutal, boring or unoriginal it may be. Nothing irritates me more than management-types saying how discovery chemists should spend more time optimizing and refining their chemistry. It makes for a nice sound bite, but I think I’ll focus less on how elegant my chemistry is and more on discovering drugs – because that’s my job.

  8. Ir dfcf3 says:

    But, but, merck uses blue leds

  9. Said says:

    Maybe alkyl amines will soon be tolerated

  10. Rule (of 5) Breaker (great nick btw – could have been mine ; ), I believe we agree. We both would like to pose questions (design&make compounds) that answer questions about the target(s) (and other properties) as fast as possible. That was my intention with the comment above. Sorry if it was unclear. I am impatient guy by nature and thus also like speed very much. But quality supersedes speed. The problem is that “quality” is so difficult to define in medicinal chemistry. How do you know for example that you should only be optimizing against one target?
    With respect to compound synthesis/design, in some cases it’ll be better to design large libraries using established chemistry, and in some cases it will be better to invest in new chemistry and new routes. Needless to say perhaps. Nonetheless, the last years (or rather decades) we have focussed to much on numbers (as for my colleague Deans comment above, I’ve got a similar one from a meeting, as late as 2002, when a very senior person said – “we’re here to fill chemical space” – I’ll never forget that moment. Epic)
    Finally, I worry a little that this paper might be used as an argument to explore new chemistry…new chemistry that doesn’t answer important questions driving drug project forward. I should stop ranting now.

  11. DrSnowboard says:

    “You cannot, I feel sure, make your way forever into target space by stringing aryl groups together like links of sausages”

    Not a follower of NS5A for HCV then ….?

  12. CMCguy says:

    Phil I too would be interested in such a survey in process chem but my sense this would have different profile and maybe a longer thick tail than what reactions get is used in medchem. I do not hold with your claim “Since they have a little bit more time to explore options, I would suspect that process chemists can take chances on sexier chemistry that will require some optimization” there are (or were) a few exceptions, such as Merck’s process chemistry group, but in most cases I think process chemists are given even less time to truly develop a workable manufacturing route so slap together as best they can and maybe squeeze in a few improvements (side exploration may be only a luxury or occasionally necessity to overcome particularly bad steps). Although often can and do look at all sorts of transformation options usually one has to avoid “sexier” reactions, frequently meaning highly complex or “exotic” conditions to apply and refine classical or tried and true reactions that can be reliably scaled. Even though the vast majority of chemistry probably could be implemented with sufficient engineering, time and expense its a rare circumstance that a process chemist will be allowed to sacrifice a fixed development timeline or even get to attempt conditions outside the normal plant operating ranges or controls. The depth of chemistry practiced can be more rewarding than repetitive analog generation but can likewise be more limited in what one can attempt never ignoring the economic, environmental and safety constraints not typically present for medchem labs,

    1. Phil says:

      CMC Guy: Thanks for the reply. Yeah, like I said, could be availability heuristic tricking me. There are a handful of examples I can think of where relatively cutting edge chemistry was applied (two that spring to mind are linked below), and they are from process chemistry groups. But that doesn’t mean that most of the chemistry used in process chemistry is cutting edge.

    2. processchemist says:

      So sad and so true: years ago 6 months (or even 12) were often allowed (and paid) for process development, route scouting included. Currently in my line of work a quick, DOE oriented optimization of reaction parameters it’s the only option. And INDA are more and more stuffed with an obnoxious quantity of sloppy synthetic chemistry

  13. Mark Murcko says:

    Interesting paper for sure. Conclusion is consistent, unfortunately, with the one we reached in our 50-year J Med Chem retrospective paper a few years ago. We gotta get more adventurous! The good news is that there are many counter-examples (i.e. very creative synthetic chemistry in pharma) so we know it can be done.

    “…the introduction of new methods for sp2 – sp2 couplings, and the adaptation of these methods to high-throughput synthesis, has had a broad impact on medicinal chemistry. Figure 5 shows the fraction of molecules containing at least one acyclic single bond connecting two aromatic rings in molecules published in JMC between 1959 and 2009. The marked increase in the fraction of molecules with acyclic bonds connecting aromatic rings over the past 15 years is consistent with the increase in “flatness” (decrease in fraction sp3).”

  14. Dean Brown says:

    Dr. Snowboard (great moniker btw). The NS5A example is explicity pointed out in the article as an example which worked, so good call on that one. The theme of the article is not to say that one cannot find drugs this way, there are examples which go back even before NS5A ans also mentioned in the text (e.g. losartan). However, the question is whether or not the chemistry space covered by these reactions is so rich in potential as to warrant the extensive use of this chemistry in drug discovery programs?

  15. Patrick Lam says:

    Regarding underutilized powerful reactions, I like to bring up Chan-Lam C-Heteratom Coupling Reaction. It is an open-flask chemistry like amide formation- great way to increase productivity to please the managment who counts compounds. It introduces heteroatom kinks in aromatic-rich molecules. It is already used in manufacturing (Eisai’s Fycompa). It is also one of the few powerful reactions that is not patented- no need to hire Buchwald students to design new ligands to get around paying royalty to MIT in order to try running B-H coupling in manufacturing of drugs. Reference- Qiao and Lam, Syn., 829, 2011.

  16. Anon says:

    But why so many different reactions in use when we have 3D molecular printing?

  17. Enough says:

    Not at all surprising. I’m always amazed that people are paid to do obvious data mining or modeling that reveals nothing new to those in the field, and nothing of value to the companies paying their salary. If they want more creativity, then stop the hand-wringing and get in the lab.

  18. me says:

    @Enough – true! There are plenty of researchers who make a career out of doing ‘obvious, run-of-the-mill’ calculations and write papers on it. I’m thinking about a guy who publishes FMO-themed papers like clockwork……

    And int erms of the original article, this reminds of a talk a few years back at an ACS from a former colleague of mine, who was at AZ at the time. He said they weren’t using enough modern chemistry, set up a think tank who came up with a load of more modern reactions that were robust and they started to proliferate – the one I remember was a C-H activation that was pretty reliable in hitting certain heterocycles.

    Needless to say, that guy is not a chemist any more, the department is shut down, and (getting back to my original comment) all that remains is a bunch of literature telling us that grass is green and water is wet.

    Also chan-Lam coupling: never worked for me. Personally I can’t think of a ‘new’ reaction that has really helped me out – since I think DAST is too old to make the cut.

  19. Patrick Lam says:

    Dear Me: Please send me an email ( and I will help you with your Chan-Lam Coupling as I have helped many worldwide.

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