Skip to Content

Two Molecules, When You Were Expecting Just One

Here’s a good short review on a subject that doesn’t come up too often in drug discovery, but can be a major headache when it does: atropisomerism. There are all sorts of structural isomers possible for organic compounds, and students in their second-year class have a joyful time learning them and keeping them straight. But what all those diastereomers and enantiomers in the textbooks have in common is that, fundamentally, they come down to invariant arrangements of the atoms and groups of each molecule. Enantiomers (like D-threonine and L-threonine), or diastereomers (like D-threonine and D-allo-threonine) differ from each other at a fundamental level of which atom is attached to which, and in which direction. Nothing can change that, without turning the molecule into another substance.

Atropisomers, though, are weirder. They happen when structures that would normally be identical through bond rotation are hindered enough for two separate species to exist. The example at right is the first pair that was ever described in the literature, back in the 1920s. If things were freely rotating around that bond between the two aryl rings, these two conformational isomers could never be seen alone. But the groups flanking the central bond keep things from being able to rotate, and you get the pair of enantiomers (mirror-image compounds) shown. They can be separated by making salts with chiral amines, and the resulting free acids do not interconvert, and have opposite optical rotations. They’re enantiomers, all right, although they don’t have any chiral carbons in their structures at all.

You can get into this situation in several kinds of structures. Ortho-substituted aryl rings shoved together are the classic way, as shown, but you can also have hindered amides that don’t rotate any more, medium-sized rings that sort of chunk back and forth between two conformations (as in this case), bicyclic structures that can’t quite get out of their own way, and more. As you might imagine, there’s a whole range of these things. Freely rotating bonds are zipping around so fast that you’ll never distinguish things, but atropisomers can interconvert on time scales of seconds, minutes, days, or years, depending on their structure and on the temperature you’re observing them at.

This neat effect can be a major pain in drug development, though. As enantiomers, the two members of an atropisomeric pair can (and in fact almost certainly will) show different effects in living systems. We’re very markedly chiral, after all (try to find some L-glucose or D-phenylalanine in your body). So what if you take a dose of a pure atropisomer, and over the hours that it’s in your bloodstream, it slowly converts to a mixture of two different enantiomers? What if it does that over a period of weeks on the pharmacy shelf? There are, for sure, conventionally chiral drugs with labile chiral centers on them, although we try to avoid that sort of thing. Atropisomerism, though, can sneak up on you, because you’re not always aware that you’ve up and made a chiral molecule.

In fact, as that review shows, what often happens when atropisomerism shows up in a lead series is that the med-chemists sigh and go back to the bench to find some way to get rid of it. There are two ways you can go – loosen things up to where everything is freely rotating again, or tighten things down to where the rate of interconversion slows down to where it can be ignored. There are successful examples of each approach. What doesn’t work, though, is just hoping the problem will go away – come to think of it, that doesn’t work too well in general.

48 comments on “Two Molecules, When You Were Expecting Just One”

  1. Isidore says:

    I learn something new every day here! If I learned about atropisomerism in my second year class I have long since forgotten about it.

    1. Joseph says:

      You can also control reactivity with this by using rotationally hindered phosphines (BINAP, et. al.) to do asymmetric hydrogenation and all sorts of other asymmetric goodness which was a significant enough breakthrough to warrant a Nobel.

      1. Excellence says:

        In the excited state binol phosphates are both more chiral and more racemic

  2. A Nonny Mouse says:

    We had this problem when making lamotrigine analogues; someone stupidly put a chiral acid in there to check….. Created a lot of work!

    Don’t forget planar chirality as well, which is also overlooked but is much less common.

    1. David Young, MD says:

      I find that potentially interesting. Is Lamotrigline isomeric? That might explain why a patient of mind developed rather severe side effects after changing from on generic brand to another generic brand and then fully recover when she went back to the first generic brand. Could it be that the second company had a racemic mixture of the drug in their tablet?

      1. Design Monkey says:

        Nope, Lamotrigine doesn’t have atropoisomers. Sterical hindrance there is way to small to create it. Original poster said Lamotrigine analogues. Likely they were with additional o-substituents.

        And all that many anecdotes about differences of pretty original and evil generic meds are bovine excrements. At best – silly nocebo effect.

        1. Hap says:

          The Ranbaxy disaster (http://blogs.sciencemag.org/pipeline/archives/2013/05/16/ranbaxy_looking_under_the_rock and http://blogs.sciencemag.org/pipeline/archives/2013/05/17/a_little_ranbaxy_example) says that all of those anecdotes may not be horse puckey, though. The FDA tests generics for bioequivalency, so that in general a generic is as effective as the name brand drug, but if the FDA doesn’t get around to inspecting them periodically (so that their processes are known to work at giving the drug they said the manufacturer says) and the generic manufacturer decides it’s cheaper to put whatever they’ve got in the pill than what they promised, then the product won’t likely be as effective as the original. It’s not the most likely cause of a drug not working, but it has nonzero probability of being the cause. (The beginning of the Ranbaxy article at the Fortune article referenced in the first link cites one such example from the whistleblower himself.)

      2. A Nonny Mouse says:

        No problem with lamotrigine; it was with larger amines on there (such as isopropyl, aryl) when the problem arose (and with other substituents on the aryl). We ended up resolving a few of these as a favour for academic researchers.

        1. David Young says:

          Thanks!… so my patient got ill from the off brand Lamotrigine for some other reason… contamination with some other drug, I presume.

  3. InfMP says:

    interesting footnote in the paper you link to:
    “The appearance of the paper at a time when I was out of touch with chemical
    literature, and the absence of any reference in the title to diphenyl had
    caused us to overlook it.–J.K.”

    I don’t think you get forgiven these days for not reading the literature

    1. a. nonymaus says:

      By “out of touch with chemical literature” he meant that he was in the trenches during the first world war. Under the circumstances, and given the tools available for literature searches in that era, the lapse is much more understandable.
      Source:
      http://rsbm.royalsocietypublishing.org/content/roybiogmem/21/389

      1. MrRogers says:

        There’s a similar comment in the first published description of genetic linkage (between the albino and pink-eyed dilution alleles in mice). That paper was published relatively incomplete due to the death of its author in France.

  4. Barry says:

    an atropisomer pair (half-life 69 minutes at 37C? at 25C?) has been reported in which one atropisomer binds HCV protease and the other binds an unrelated protein. Here, it’s hindered rotation around an amide, but not around the bond you (ok, I) would have thought

    http://pubs.acs.org/doi/abs/10.1021/jm401202a?journalCode=jmcmar

    1. tlp says:

      yup, it’s in the review

  5. Kelvin says:

    Interesting subject. I remember being taught by Cornforth about all this stuff at Sussex Uni. 🙂

  6. Marcin says:

    Very popular mistake to call a carbon “chiral” . It is a “center of chirality”. Even some professors teaching undergrads are perpetuating it.

    1. Derek Lowe says:

      That is a more accurate way to put it

      1. Peter Kenny says:

        I think that the chirality of atropisomers (and allenes) is termed ‘axial chirality’

    2. bob says:

      Besides satisfying your pedantry what benefit does the excessive verbiage offer that the concise form does not?

      1. DrOcto says:

        The carbon atom is not chiral (i think?, perhaps at a nuclear level it might be, who knows), it is the arrangement of groups around that carbon that is chiral. Bad grammar/punctuation can kill.

        1. tangent says:

          Having trouble coming up with an example of an erroneous conclusion that might be drawn. What have you seen?

          1. AR says:

            Chirality and symmetry breaking means different things across different subjects and there’s not reason to not be as precise as possible. If people aren’t comfortable with that then it might be an ego problem as opposed to a chemistry problem

      2. AWildPostdoc says:

        The whole symmetry/chirality explaintation given to O-chem undergrads is brutal on a good day. I’ve seen people break down and cry in frustration.

        The classic example commonly encountered in lower level chemistry courses are meso compounds. You’ve got stereogenic centers but due to symmetry the molecule is achiral. Calling those centers “chiral carbons” is confusing and in that case wrong.
        The sloppy inaccurate term “chiral carbon” makes a topic most find confusing and difficult on a good day harder than it has to be. Unfortunately enough people use it that its widely accepted.

    3. milkshaken says:

      even more maddening mistake is to use word chiral instead of enantiopure (or optically pure). Our undergrads and also some foreign postdocs working in medchem liked to call “chiral” any building block that was available to them in enaniopure form; if they used racemic material they said it was “unfortunately not chiral”

      1. Humulonimbus says:

        The use of “chiral” in place of “asymmetric” (e.g. chiral synthesis, or chiral catalysis) makes my skin crawl.

        Don’t get me started on “enantiospecific.”

  7. Peter Kenny says:

    There seems to be a paradox here in that problems caused by the presence of enantiomeric conformers are assumed to go away provided that they interconvert rapidly enough. A long half life (10+ years) is likely to be necessary for development of a single atropisomer and it would also be necessary to think about the temperature at which the drug is stored. Atropisomer interconversion may be slower in solid state. I don’t know if there is any precedent for acid catalysis of atropisomer interconversion but maybe this is something that somebody has studied.

  8. Martyn says:

    An interesting example is Martin Kuehne’s work with homologues of vinblastine. They can be converted from the inactive atropisomer to the bioactive one, which would be a really good prodrug technique if it didn’t require heating the patient to ~100 degrees C…

  9. Uncle Al says:

    An acyclic tetrasubstituted methane has four freely rotating, rigorously identical substituents, CR_4. It is chiral. Give an example

    1. Karishma Chaggit says:

      K4 carbon crystal? Dying to know.

    2. guest says:

      Each substituent is fluorobromochloromethyl

      1. Uncle Al says:

        BINGO! The enantiomer of CR_4 is CS_4. Fluorochloromethyl lessens steric effects.

        Geometric chirality cannot be measured, but it can be calculated on a normalized scale of 0 (achiral) to 1 (perfectly chiral), DOI:10.1063/1.532988 and DOI:10.1063/1.1484559, QCM software. The 11 pairs of enantiomorphic crystallographic space groups are perfectly chiral (e.g., alpha-quartz and gamma-glycine), as is the carbon skeleton of

        http://www.mazepath.com/uncleal/schwart3.png

        D_3-trishomocubane, ~isosteric to a benzene ring, pulls large numbers. Russia spent much money finding no agile pharma. Phenylalanine vacuum structure (uncharged) calculates 0.058600

      2. Karishma Chaggit says:

        I don’t think this is correct. If the 4 stereogenic carbons around the central C are R,S,S,S then there is a C3 axis of symmetry, if they are R,R,S,S then there is an improper axis S3 (bisecting the angles between the substituents of like stereogenicity) which again renders the molecule achiral. Can’t see any other option here. What am I missing?

        1. Uncle Al says:

          “four freely rotating [re latched B(CF_3)_4 anion, point group T not T_d. T_h], *rigorously identical* substituents.

          D_3-trishomocuban-2-nitrile, CHI=0.884725 with a ~4 Debye dipole moment. Vacuum supersonic expand 3:1 R/S (literature synthesis) to 5 K or lower rotational temp (prolate top), then molecular beam into a chirped-pulse FT microwave spectrometer (e.g., Melanie Schnell). Canon says the rotational spectra are exactly identical and exactly superposed. Baryogenesis (Sakharov conditions’ absence of post-Big Bang antimatter) says they aren’t. A slight lopsided divergence puts coal in both physics’ and chemistry’s stockings. Enough.

          1. Karishma Chaggit says:

            I see. I forgot the SSSS (or RRRR) version. Funny that T point group is always chiral, even though it looks more symmetrical than the other two versions. Thanks for these interesting thoughts (and more).

  10. Peter S. Shenkin says:

    Kurt Mislow (RIP) redux.

    1. Derek Lowe says:

      Invoking both Cornforth and Mislow in these comments rolls out some folks who certainly knew their way around chirality questions. . .

  11. Emjeff says:

    This is very interesting. Are there any currently-marketed small molecules with this property?

    1. Marcin says:

      Idelalisib

      1. kriggy says:

        WHere is the chiral axis in Idelalisib? Doesnt look like atropoisomer..

    2. SJW says:

      Vancomycin

    3. Calvin says:

      Lilly’s Notch inhibitor, LY3039478, currently in clinical trials.

  12. Labrat says:

    Most drugs are like this in the interiors of the cell, where molecular crowding reduces the effective rate constants of molecular switching. Showed this very well in a theortetical write-up. My PI said, “who cares, get back in the lab, im going to a conference to drink”. Now, im doing my post-doc at mickey-ds b/c he would not write a rec letter after a nat paper.

  13. Gordonjcp says:

    What does the thick bit on the side of the ring mean, for us non-chemists trying to remember high-school Chemistry classes from 30-odd years ago?

    1. Derek Lowe says:

      That means that it’s supposed to be seen as coming out of the page at you (thicker because it’s closer).

  14. David Edwards says:

    And of course, the classic example of a molecule that causes trouble, because it interconverts between the R and S isomers in vivo, is Thalidomide. One isomer is biologically inactive, the other is a ferocious teratogen, as an unfortunate number of pregnant women and their offspring found to their cost.

    1. Derek Lowe says:

      That’s actually a tough contention to prove, because of the lability of that chiral center – see Box 1 in this article:

      https://www.nature.com/articles/nrd915

  15. Non-millenial says:

    The figure in this blog post is a bit confusing to me. Isn’t the way to assign axial stereochemistry by looking down the bond (similar to how we assign chirality to allenes) and the doing the typical “largest to smallest” substituent check? In the figure, there are two instances of nitro and carboxy groups, so it’s hard for me to understand how these are non-superimposable mirror images. It’s been a few years since I had to do this, so I’m probably wrong.

    1. Non-millenial says:

      Never mind- I read the paper & see my error.

Leave a Reply to guest Cancel reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.