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Travel

Traveling, so no chance to do a decent post today. But that gives me a chance to ask a question that I bring up once in a while: are there topics, recent papers, news, that haven’t come up here (or not recently) that deserve some attention? I’d welcome suggestions (as always), with the proviso that there will probably be enough to keep me busy for two months (!)

63 comments on “Travel”

  1. Min says:

    I think a recent essay from George Whitesides about his perspective on the future of organic synthesis worth some attention.

    Complex Organic Synthesis: Structure, Properties, and/or Function?
    https://onlinelibrary.wiley.com/doi/full/10.1002/ijch.201800016

    1. Anonymous says:

      Good insights of Whitesides on what and how the ‘field of organic synthesis’ should evolve. However, I am afraid that with out the proper organic synthesis community ( which neglects the function, as per the author) that focuses on just building the structures it is difficult to think of synthesize the structures with or for functions. Organic synthesis (synonymous with method development/NP synthesis) is an enterprise that points to the gaps in the methodology and helps with developing tools to build the structures with the functions.

      It is analogous to support (visit?) Home-depot (enabling tools/raw materials/ just the structures) and builders if you want to build homes where you can live ( structures with function). How could every one think of building mansions when building houses on their own is questionable? Organic synthesis is a skilled trade…..synthetic chemists are molecular architects and engineers. One will have to learn the craft the hard way under apprenticeship, as he alluded to, in to foreseeable future even though there will be AI and machines to outsource some of hard part. However, it’s a good suggestion for graduate students to learn other fields such as biology, material science etc.

    2. Romain Lepage says:

      Ooh yes, I would love to here some of Derek Lowe’s comments on George Whitesides!

    3. tlp says:

      Classic Whitesides 🙂
      I think he has been communicating this message for many years now. It just gets more prophetic with each passing year.

    4. Chris Phoenix says:

      I’d be very interested in Derek’s (or anyone’s) take on combining molecular self-assembly with a post-assembly step of binding the assembled product. Photo-activated covalent bond formation? Zinc fingers, and then introduce zinc after assembly? Other methods of making the structure more durable and/or rigid? Medicine might not have much use for large rigid molecules, but other fields (catalysis? X-ray diffraction scaffolds?) might.

    5. tlp says:

      Hey, the whole issue is interesting and full of interesting (and open access) thoughts!
      I particularly liked this supposedly humorous passage by Anat Milo “Overall, from 1954 to 2011 the number of steps required for constructing strychnine decreased from 29 to 9. Put in terms of the exponential growth plot depicted in figure 1, the inverse of the number of steps reveals a doubling time of just below 25 years. If this trend holds, by 2090 strychnine will be prepared in one step, which, in homage to AI futurists, could be referred to as the singularity.”

  2. SIrWired says:

    We need more “Things I Won’t Work With”! Can’t believe this is even a question! 😀

    1. SIlverlake Bodhisattva says:

      Yes, more TIWWW please!

    2. Derek Lowe says:

      I knew that one would come up quickly!

  3. Jeff says:

    Yes indeed, more “Things I Won’t Work With” or “Things I’m Glad I Don’t Do”. If I’m having a rough day, a short read about Satan’s Kimchi quickly puts my problems into happy perspective.

    1. Kevin says:

      …more Things I Won’t Work With or Things I’m Glad I Don’t Do…

      With the relentless, depressing drone of cable news, there is now nothing that Derek’s tortured soul won’t work with and isn’t glad to do just to distract himself.

      The lack of TIWWW posts is actually a cry for help.

  4. Anon says:

    “Cancer researcher at The Ohio State University resigns following multiple misconduct findings.” – Science, March 30th (And relevant to some recent Pipeline discussions about bio affecting chem. And still having a job elsewhere.)
    “Duke’s mishandling of misconduct prompts new U.S. government grant oversight.” – Science, March 23rd
    Plagiarism charges at McGill / Auburn – Prof says it was “innocent mistake”; then says, “I want the scientific community to be better, particularly at a time when cheating and lying have become the norm.” – THE *NORM*? – Retraction Watch, April 2nd

    I guess ad nauseum is the new norm.

  5. George Freeh Comey says:

    Topic suggestion : your recommended top science-fiction novels/stories, and movies.

    1. Derek Lowe says:

      That’ll be a good post for a Friday one of these weeks. . .

      1. David Edwards says:

        If you’re looking for science fiction to cover in your blog, a good start would be James Blish’s Cities in Flight. Not least because in Book I of the set of four, there’s a nice discourse on the travails of drug discovery and the inner working of the pharmaceutical industry that may well be in accord with comments here posted much more recently (this work is of early 1970s vintage, but is still a cracking read if you’re willing to exert some effort on it). There’s also, later in Book III, a discourse on the harrowing consequences arising from pharmaceuticals being used for currency exchange purposes. All of which should be lighting your fire here. 🙂

  6. Mad Chemist says:

    Perhaps some comments on catalytic diamination and its potential implications for pharma? See below:
    https://pubs.acs.org/doi/pdf/10.1021/jacs.7b01443

    1. Design Monkey says:

      Recently there is a lot of papers about “stick two whatever X,Y functional groups onto alkene” and often with label “this fancy “new” chemistry will not work on anything, but styrenes”.

      So far most of them are just meh, routine sweeping up the floors of synthetic methods.

      1. Mad Chemist says:

        Diamination has been the Holy Grail of organic synthesis for some time. As for adding things across a double bond, there are some groups that really just do styrenes, but more and more there are papers where g these reactions can be done on non-conjugated double bonds with reasonable functional group tolerance.

        1. Cato says:

          … why is diamination the holy grail?

          1. Sans sheriff says:

            It’s just the thing hackademics say to justify their uninteresting impractical methods. “proof of concept” is another favorite.

        2. Design Monkey says:

          That holy grailiness of diamination as reaction is only in showing off that ” oh, yeah, we did it in sorta one step (with frikking limitations and only on styrenes)”

          If one needs diamines as products , then they are not anything especially inacessible or holey-grailey by other methods.

          You should distinguish between organic chemistry ( you need to publish, and no one cares if the new method is useless or impractical or so limited in scope that nobody in the world ever will use it) and medicinal chemistry (you have to produce product, and no one cares the tiniest, how it was made).

        3. me says:

          Diamination is the holy grail of organic synthesis?

          You’ve been drinking too much of your PI’s coolaid.

          1. Fauxtoredox says:

            You’re right. The true holy grail is replacing cheap stoichiometric reagents in robust thermal reactions with expensive iridium photocatalysts and proprietary photoreactors.

    2. Derek Lowe says:

      I’ve got a couple of other “neat reaction” papers sitting in the queue – I may combine them into one post soon.

  7. Li says:

    There’s definitely been some interesting (exciting?) papers recently about the use of proteins, RNAs, and DNAs and more relevantly to this blog our expanding ability to tailor them for medicinal purposed. I check in here between weekly and monthly so perhaps I’ve missed the mention of them.
    Another area I’d be interested in is the changes in what constitutes a formal chemical education (up to the BS, up to the PhD) on average now-a-days.
    I’d say the third area (hey, you asked) is links to ‘expert’s’ blogs (like yous) in unrelated but still quantitative science/engineering disciplines – when the “News of the Day” merits it. A few examples, since this is more than a bit vague: 1) Is it really that difficult/dangerous to produce a Novichok or Novichok-like 2k organophosphate? or 2) NASA ((over?) a year ago now) claimed their research on a electric propulsion drive produced a (small) net force without use of propellant. If true (which I doubt, but I’m not competent here) it seems to be contrary to the (known) laws of physics. Seem worthy of a post/link to a more critical analysis?

    1. Li says:

      Sorry for typos.
      …and more relevantly to this blog – comma – … purposes.
      ..(like yours)…

    2. tangent says:

      I’d love to hear some other blogs like yours in different industries (or, hey, academia or government or law or whatever).

  8. 123 says:

    Recent trend is to find a old methodology published in old obscure and non-English journals and sell it under the name of new methodology by carrying out in fancy way, which amounts to dodging the original citation and is a sort of plagiarism. Probably you can do a post on it ” should have been cited” and commentators can pitch in with their own collections of such incidents so the reviewers and authors would be alerted to see whether all the relevant work is cited.

    1. Derek Lowe says:

      I’d be glad of some examples, and it sounds like you might have some (!)

  9. Ben says:

    A discussion about the future of carbohydrates both from a synthetic point of view as well as importantance in chemical biology.

    1. Derek Lowe says:

      My PhD work involved a lot of carbohydrate-based synthesis, so I always have a soft spot for them.

      1. Ted says:

        I have my own soft spot for carbohydrate work, and I usually carve a little time out at the Natl. ACS meetings to catch a few CARB talks. Over the last few years Bertozzi’s work with glycocalyx editing has been a fascinating story to see unfold, and it looks like it’s starting to pick up speed. Siglecs/sialyl recognition reads a heck of a lot like the PD1/PDL1 story, assuming it isn’t simply a different chapter in the same book… I’d love some posts that put this work into the larger context.

        -t

  10. Calvin says:

    OK, this one is boring but could have profound implications for pharma in particular.

    EU GDPR (only a wiki away). Whilst the legislation is aimed at internet companies, it’s actually going to have very broad implications on clinical trials and how we share that data or deal with any patient data/samples etc. Huge fines if you don’t comply and extra-territorial so will drag in a lot of non-EU situations; even US companies doing work (with companies or academic institutions) in the EU or with EU citizens will have to comply. There is already a nice (expensive) industry around GDPR compliance.

    If you’ve not heard of it (it goes live in late May) then prepare to hear an absolute tonne about it in the coming months and potentially(?) complicate what we do quite significantly…….

    1. NotAChemist says:

      Whether or not the GDPR applies to US companies who have data about EU citizens who are outside the EU is, I believe, undecided, and I think it extremely unlikely that they will be found to be in-scope.

      1. Calvin says:

        GDPR is absolutely extra-territorial so US companies will have to comply if they have any EU presence. So US companies that have zero corporate presence in the EU are not in scope, but everybody else is. This is how the EU have dragged Facebook, Google etc into scope; US companies with a EU presence. But you are right that there is still considerable uncertainty to say the least.

  11. MP says:

    How about high-throughput screening as is currently being used by NIH and EPA (ToxCast, etc.) for predicting toxicity and mode of action for environmental contaminants?

  12. Rhodium says:

    What should the grad chemistry curriculum look like?

  13. Wavefunction says:

    Is a hot dog a sandwich?

    1. A. Nonymous says:

      Asking the real questions 😀

      1. sgcox says:

        Sandwich is flat, hot dog is round. So no.

        1. AR says:

          What do you think about: i) Ice cream sandwiches, ii) Tacos

          1. If you put the dress into a bun, what color would it be?

          2. sgcox says:

            Should also satisfy the second criteria as formulated by Lord Sandwich:
            – Can be safely consumed without interrupting the flow of the game of Wist(Bridge)
            So probably no in both cases..

  14. Peter S. Shenkin says:

    I’m not an organic chemist, so maybe this is off-base.

    It seems to me that given all the emphasis on completing a complex synthesis, and the variety of things one often to try to get some reactions to run properly, there has been very little retrospective effort focused on why, say, solvent X worked when solvent Y did not.

    I remember one lengthy synthesis discussed here where a grad-student who had worked on a key step said that he indeed tried everything he could think of, until he found something that worked. His approach sounded completely Edisonian.

    It seems to me that something could be written about this. Are there any labs trying to figure out why Z worked where A through Y were tried but did not? It seems to me that if results of this nature could be deeply understood, insight would be gained that would at least reduce the number of solvents (or other variable reaction conditions) that it would be necessary to try in order to successfully run or optimize at least some reactions.

    If anyone is doing work like this, it would be great to hear about it. And if not, perhaps we could ask why not. I guess the obvious answer is that one road to glory is still synthesis of a very complicated natural product, not the gory details of the individual steps; but still, just as the Woodward-Hoffman rules brought new and useful insight into the stereochemical course of certain reactions, this kind of study might bring useful insight into the optimization of reaction conditions.

    1. tlp says:

      As far as I understand, the problem you’ve described is in the realm of process chemistry and chemical engineering. There is a general-purpose statistical framework for optimization of conditions – DOE (for design of experiment). It also deals with meta-optimization, i.e. how to find the optimal conditions with the least amount of experimentation. If really necessary, process chemists can go into very fine details of what happens in the reaction mixtures – e.g. formation of solvates of different stoichiometry upon ‘aging’ of the reaction mixture, which leads to single-digit percentage difference in yields or even smaller difference in product purity.
      The problem with this kind of knowledge is that it’s not easily generalizable across broad range of substrates/reactions/conditions. Sometimes methyl group in the wrong position can break all correlations.
      So it makes sense to invest the effort only for a good return, i.e. for making really useful molecules. The task of synthetic chemists is more to figure out what molecules are likely to be useful and make them no matter how.
      Anyway, I’d read Derek’s thought on that, too

  15. tlp says:

    There seems to exist a void in chemistry theory – somewhere between Schrodinger equation/DFT/etc. computational chemistry and emergent thermodynamic properties. I wonder if it shrunk any bit in the last decade and who’s leading the effort.

  16. Project Osprey says:

    The cyclic trimer of carbon dioxide (trioxanetrione) was synthesized fairly recently

    https://pubs.acs.org/doi/10.1021/acs.joc.6b00647

    Obviously not an important discovery but interesting one, and a nice example for discussions on structures that you might or might not expect to be stable

    1. tangent says:

      Fun paper, but geesh, the things people think they have to put in to their Introduction sections to keep up with the times.

      “As a product of combustion and respiration whose accumulation in the atmosphere has become a cause for significant concern, carbon dioxide has been the subject of much research directed at its reutilization. […] This could be raised to 100% if a CO2 self-fixation chemistry could be developed.”

      /eyeroll

      “As will be shown, compound 1 does not possess the stability for facile isolation and storage.”

      /Iamshockedtofindthatinstabilityisgoingoninhere

      1. Project Osprey says:

        Well I suppose someone is funding this and its hard to just say “we made it just to see if it could be made”

        What I like about it is that any undergrad might look at that structure and assume that its perfectly stable. Cyanuric acid is fairly similar and that’s rock-solid.

  17. misterscampers says:

    Efforts by the Doyle lab to use machine learning to predict reaction yields based on substrate functionality.
    DOI: 10.1126/science.aar5169
    DOI: 10.1021/jacs.8b01523

  18. Andrew says:

    Do you have any thoughts on the evolving influence of ICER and its use of cost-effectiveness thresholds and budget impact assessments in order to recommend a value-based price. Certainly this group is getting a lot of press.

  19. cancer_man says:

    You criticized Elysium in the past but do you have a new opinion after they published their NR/pterstilbine Basis supplement that showed healthy 60 to 79 year olds (n=120) walked 8 percent faster on a 6 minute walkin test and did 8% better on a balance test? Also, what are your thoughts on the recent U of Colorado-Boulder human trial that showed NR improved arterial health among those with mild hypertension?

  20. Defense Date Scheduled says:

    I’d like to see more commentary about the latest approvals and drug candidates and how companies are doing, especially out in Boston.

  21. Isidore says:

    Your perspective on how improvements in analytical technology and instrumentation have (one hopes) helped you with your work would be quite interesting to have. Especially with regard to being able to detect and characterize minor impurities, which sometimes end up carrying much of desirable or undesirable activity.

  22. Ted says:

    At some point, machine learning of organic synthetic “rules” will be hampered by the lack of reported failed reactions in the literature. Documenting the stuff that doesn’t work, in a high throughput format, seems like exactly the sort of thing we should be making our robots do for us. Even things like solvent screens of known reactions. It’s interesting to think of building libraries of reactions where failure is the desired outcome, and then adding in a few positive controls to make sure everything is mixing/dispensing/sampling correctly…

    I recognize that there are plenty of failed reactions in the literature that simply need to be called out… but that’s a separate curation problem that needs some empirical support.

    -t

  23. Frank says:

    What about academic drug discovery? It has been about 15 years since the NIH started pumping money into this. Has it worked out ?

  24. Retro sinner says:

    At some point it will be possible to apply machine learning and predict routes, conditions, yields but maybe not yet. Whitesides is also right , we need to consider WHY we study ‘X’ but there will always be a need for more tools because godzillamycin can’t always accommodate high pH ester hydrolysis. Maybe we need to consider necessity vs vanity project. Ultimately, society (or NIH, EPSRC etc) need to decide what the realistic proportion of application vs. discovery is.

  25. Retro sinner says:

    For what it’s worth, I also agree with the analysis that olefin diamination may not be the holy grail of organic synthesis. Doesn’t mean that someone won’t find it useful but are we talking syn/anti/stereo/regio/chemospecific, can I do it in an RBF, do I need your proprietary catalyst, does it accommodate anything other than bare styrenes, will it work on tonne scale, is it subject to environmental restriction? I have no problem with PR but should I really care or be interested if I don’t need it now?

  26. Retro sinner says:

    Thinking about future blog topics, i think it would be interesting for Derek to consider what was historically presented as useful or appropriate undergraduate content for a chemistry degree but might now be viewed as dated, redundant or of limited duration. From my own experience as a late 80’s PhD student I might offer Cr(VI) reagents, OVAT optimisation, elemental analysis and maybe even PGM chemistry From early industry experience i might also add combichem.

  27. A Chemist Has No Name says:

    Your perspective on the rise and decline of Biotech companies, and their transformation into “larger pharma” – in particular and how share prices can be greatly effected by press statements. Especially after your post on Theranos, your view on Redx Pharma and other UK Biotechs would be insightful.

  28. Moz says:

    How about some focus on Alzheimer’s – particularly the role of nitration and oxidation as the true villains…

  29. Kiss the Chemist says:

    How about nerve agents in general and Novichok in particular?

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