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Modifying Natural Products, And How

The field of late-stage modification of complex structures has seen several advances in the last few years, and this is just the sort of thing that medicinal chemists tend to be interested in. We like one-step transformations (which organic chemist doesn’t!) and we tend to have large collections of compounds that have already been made. The idea of running a bunch of these past some new reagent and producing a whole new pile of chemical matter is quite appealing.

For that to work out, several conditions have to be met, though. The reaction conditions have to be compatible with a huge variety of functional groups, and ideally they have to be able to transform a wide variety of molecules as well. And finally, these new reactions have to make something interesting. To pick a couple of examples, going through the collection with a big bottle of acetic anhydride is probably not the answer. You’ll acetylate OH and NH groups, which are pretty common, but the products you get are either not likely to be good drug leads (O-acetyls get cleaved readily) or are already represented in the collection (N-acetyls probably have amides of the same sort already made). On the other hand, if you have a reagent that selectively turns tertiary CH groups into CF, that’s worth a look. There are probably quite a few of those compounds in your collection, and the odds of their fluorinated analogs being in there are very small. Once fluorinated, the compound properties are likely to change quite a bit as well, so I would definitely be up for a mild, selective, high-yield fluorination pass.

This new paper (a free PDF may be available here) is a pretty wild addition to the toolbox. Thomas Hoye of Minnesota (and co-author Sean Ross) are applying the group’s favorite hexadehydro Diels-Alder benzyne reaction to natural product structures. Benzynes are pretty hot intermediates, and HDDA is an unusually mild route into them. The classic benzyne reactions are low-temperature affairs with honking strong bases, which is not what you’d want to expose a complex natural product to, but they can handle the thermal HDDA conditions. And being reactive creatures, the benzyne intermediates can form products with phenols, alcohols, amines, furans, carboxylic acids, and more, and they can also do interesting thing like unzip the DABCO bicyclic amine to a piperazine.

A couple of these products are shown from the reaction with estradiol and its acetate, with the HDDA additions in red. That piperazine one is actually produced in 80% yield, which is remarkable. Similar thinks happen with Vitamin E and other phenols. The real fireworks start when more complex natural products are exposed to the HDDA conditions, because all sorts of unusual ring openings and rearrangements start up. Reserpine, for example, is already a fairly large and complex alkaloid, but I can guarantee that you haven’t seen anything like the ten-membered ring that comes out of its reaction under these conditions. (“Nuc” is one of several traps, for example, a benzotriazole, and that product forms in about 35% yield). The paper shows unusual products from quinine, scopolamine, brucine and others, but I’d be all morning trying to draw them.

I think it’s safe to say that this paper only begins to show the variety of things that can be produced under such conditions – they would yield a compound library like no other, even if you don’t go up to the brucine-functionalization level. Just HDDA-ing a range of simpler substrates would give you a lot of odd variety, it seems safe to assume. Not all of them would be suitable additions to a serious drug screening library, but a surprising number of them would be worth a look, and you’d most certainly be exploring new chemical space. This work is another reminder that such space is large indeed.

21 comments on “Modifying Natural Products, And How”

  1. Anon says:

    Professor Hoye was a consultant for a pharma company I once worked for. He was the greatest. Not only smart and personable but only cared about helping you with a practical solution to your problem vs. showing off how smart he was.

    Hats off to you professor Hoye.

    1. Anon2 says:

      He was my O-Chem prof in undergrad. Ditto to what @1 Anon said, Hoye is one of the nicest, smartest people I’ve ever met! Glad to see his group be so successful!

  2. David says:

    Noting your use of the word “mild,” Derek, knowing your deep love for high concentrations of Fluorine…

    Sounds like a process with fascinating possibilities, although I look at that ring and wonder how long until someone tries to do C10F20.

    In an while-I’m-on-the-other-side-of-the-plant way, can you explain why no lunatic has made a N6 ring, because a N6F6 ring sounds interesting, and to my mind, more stable than the N6 ring alone?

    1. Mad Chemist says:

      An N6 ring, while predicted to be aromatic, is also predicted to be highly unstable due to electrostatic repulsion from the lone pairs on the nitrogens and possibly donation into antibonding orbitals. I agree, it would definitely be cool, though.

      1. David says:

        Could you rectify that instability with bonding something like F to the N, getting rid of the double bonds and this evening out the charge distribution?

        1. Mad Chemist says:

          I’m not sure, but I think that would make it worse. You’d lose the aromaticity right off the bat, and I think the lone pairs would be even better positioned to donate into antibonding orbitals. Also, as a general rule, N-N bonds get weaker as the bond order decreases, which is why N2 is so stable. The electronegativity of the fluorine atoms would help, but I don’t think it’d be enough. I think the best way to stabilize an N6 ring would be as some sort of ionic compound, but that’s just a hunch.

  3. anonymous says:

    Seems like fishing expedition to me. We also call them “unguided missiles” meaning not knowing where it is going to land or the biological targets thereof, if any when tested. An organic chemist in me is impressed but as a medicinal chemist, Hmm.

    1. Dr CNS says:

      Structures are novel and complex, chemistry is creative, and this is coming from an academic group… nothing wrong with it, if you asked me.

      I look forward to someone running them through a phenotypic screen and seeing what comes of it…

    2. Mol Biologist says:

      IMO fishing expedition at Caenorhabditis Intervention Testing Program (CITP) would be successful If the compounds may have ability to extend lifespan of tiny worms.
      http://www.nature.com/articles/ncomms14256
      However, it would hard to modify them without understanding biological functions neither for Thioflavin T nor for others which Derek mentioned in his post. Since, there is other well known effect of Thioflavin to bind amyloid fibrils.
      ghttp://pubs.acs.org/doi/abs/10.1021/jp207118x

      But we all have a hope that one day it may form the basis of human drugs that can combat aging and age-related illnesses such as Alzheimer’s and Huntington’s disease, cancer, and other.

    3. Anon says:

      Evolution is also a fishing expedition, and it has worked rather well. So as long as there is enough diversity, and screening is fast and cheap, why not?

      1. Mol Biologist says:

        I would rather not say that the evolution is cheap and fast.
        IMO these tiny worms have tools to use the drug as advantage and it was acquired during evolution but it may have another functional importance in human.

  4. Anon3 says:

    Great post, Derek. Prof. Scott J. Miller has also established that chiral catalysts can override inherent reactivity of the same functional group present in a natural product for site-selective modifications amenable to medicinal chemistry.

    See several references in this list: http://millerlab.yale.edu/publications

    #66 is a great starting point. #144 is a review.

  5. anon says:

    I think you should say ” Sean Ross of Minnesota (and co-author Thomas Hoye)”

    1. DrOcto says:

      Agreed. Most likely Hoye was the man with the plan, but at the end of the day it was Sean Ross that got it to work, did all the chemistry, the data analysis, and I’m guessing also the first draft of the paper. Hats off to both of them for some excellent chemistry.

  6. Cato says:

    It’s neat, but I wish they had demonstrated or chosen a benzyne that would be amenable to some sort of transformation into a (smaller) useful handle, rather than just throwing on this large group

  7. gippgig says:

    No, not a free pdf at the link.
    Seems like it should be possible to trigger this reaction photochemically – just find the right wavelength. Would this reaction also work with an enediyne?
    On the side topic, note that N6 could easily break up into 3 N2 molecules, probably with little or no activation energy. Wonder if it could be stabilized as a borane adduct. Wonder if you could make a borane adduct of N2. Anyone look into that?

  8. Anonymous says:

    Anthranilic acid (2-aminobenzoic acid) is a convenient source of benzyne via diazotization and elim of CO2 + N2. Elimination requires mild heating, just like the Hoye reaction. I’m not sure, but I think that you probably diazotize in one vessel, do some cleanup (remove excess reagents) and add to the natural product flask. Anybody ever semi-isolated the diazonium?

    Two major drawbacks of using anthranilic acid: (1) Not easy to add diversity to the benzene ring; that’s much easier by Hoye’s alkyne couplings. (2) Not easy to get anthranilic acid anymore because it’s on the DEA list of controlled substances because you can use it to make Quaalude, etc.. I worked in an old lab that had a 1 kg jar of anthranilic acid sitting on a shelf, unused. It must have been purchased in the 1960s or early 70s. (I don’t remember if the label had a zip code or zone on the manufacturer’s address.)

    1. anonymous says:

      Anthranilic acid is a simple precursor for plain Benzyne. The preparation of substituted Anthranilic acid by in itself could be a problem to make other substituted benzynes. The vicinally placed trimethylsilyl and the triflate group in aryl system provides the mildest conditions for the generation of benzynes and trapping thereof. One can take advantage of directed metalation strategy popularized by Victor Snieckus and others to make aryl silyl triflate intermediates easily to access other exotic benzyne precursors!

      1. SPR says:

        These Anthranilic acid derivatives are shock sensitive though. There have been reports of some pretty destructive explosions that i have heard about using these on large scale (>10 g) usually fine for small scale work though.

  9. Curtis Tyree says:

    Derek,
    I propose that the chemistry community adopt your terminology of “honking strong bases” as those that dissociate completely at 0.01 M or less. List would include calcium hydroxide, strontium hydroxide and barium hydroxide.

  10. Sean P. Ross says:

    Derek,
    I am glad you enjoyed the paper! We have been working on this for quite some time and it is great to see that people in the business of making molecules think that it could be useful! Keep your eyes out for our work utilizing small (and far less complex) amines to make some pretty interesting molecules.

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