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Some Natural Product Weirdness

Let us take a moment to gaze upon the weirdness of natural products. For an organic chemist, these things can at times be startlingly weird, with structures that keep bringing on the “Well, I never would have thought of that” response. I collect especially odd ones as I see them in the current literature, so allow me to unload a few.

First off is populosone, made by the desert poplar (Populus euphratica) for reasons of its own. You chemists will have seen plenty of bicyclooctane frameworks over the years, but I’ll bet you’ve never seen one with a ten-membered ring fused to it. Come to think of it, how many of us have ever seen a real ten-membered ring fused to anything else or not? That’s smack in the too-hard-to-form ring size zone, and you really don’t come across them much. I’ve never made one in my life, at least not on purpose and thus not that I’ve ever known that I made. (Edit: I’d originally hosed up its stereochemistry, although not its weirdo framework; it’s now fixed).

Then you have Dragocin B, a marine natural product. The keen-eyed will have spotted that origin already because of that rogue chlorine – marine organisms often slap odd chlorines and bromines in, and that’s a particularly odd place to put one. The rest of the structure is rather funky as well – you’re generally not used to seeing furanoses (or any sugar with the anomeric center and the C-6 hydroxyl both tied back onto the same partner to make a large ring (nine-membered in this case). Interestingly, this is closely related to an antibiotic compound isolated from a Streptomyces species; some rather different organisms have hit on basically the same idea.

Drawing these things can be a bit of a challenge, I should add. I found the easiest way to ChemDraw Dragomycin B was to start with the nine-membered ring, then wipe out one carbon and wedge in the furanose, and work from there.

Too many chiral centers, you say? Then check out Pusilatin B at right. This looks more like a materials science experiment gone wrong than it looks like something that came from a Japanese liverwort, but the plant makes a whole series of these beasts by coupling two molecules of the simpler but still industrial-looking Riccardin C (which is also produced by a species of Siberian cowslip). Liberal arts types will recall that Ariel from Shakespeare’s The Tempest envisioned taking some break time in a cowslip flower; these compounds might have made her rethink.

All right, one more. This is a somewhat older compound, Telomestatin. Would you have thought to make a ring out of eight separate azoles heterocycles? You would not. And even if you did, you wouldn’t have tossed in those little natural-product grace notes like those two extra methyl groups, or the thiazolidine that suddenly turns the whole thing chiral.

This is another gift from the ever-inventive Streptomyces genus, and it was discovered as a telomerase inhibitor, of all things. Drawing it is surprisingly easy – you start off with the horizontal bond at the top, and when you put the next two five-membered rings in you rotate them to force horizontal bonds. Then copy that unit, flip it horizontal, and draw the two vertical bonds, aligned the two halves until they look right. After that, it’s just slapping in heteroatoms and extra bonds; it’s basically a blown-up eight-membered stop sign. I tried pasting in the SMILES string from that Wikipedia article in an attempt to save time, but as often happens with funky structures, it came out looking so ugly that it was painful. You’d have to tie a pork chop to it to get a dog to play with that version, to adapt a phrase from my Arkansas upbringing, so I did a quick redraw.

That should be enough head-scratching for a Monday. I have plenty more of such things in my files, so I’ll bring out more alien oddities another time. Enjoy!

 

45 comments on “Some Natural Product Weirdness”

  1. Uncle Al says:

    Ladderane lipids form anammoxosome membrane so nitrate becomes dinitrogen without annihilating the bug. I eagerly await The Green New Deal demanding we grow rocket fuel in activated sludge (recycled Congressional Record).

    http://blueline.ucdavis.edu/Images/LadderaneLipids.jpg

    1. zero says:

      We collect methane from plenty of renewable sources. We could do so with hydrogen if we wanted. Even rp-1 could be synthesized if necessary, but the energy wasted in the process and the trivially small quantity required suggest it will be fossil-sourced for as long as we use kerosene in our first stages.

      The future of rocketry is hydrolox or methalox with IVF, meaning no more hydrazine for RCS and no helium for ullage.

      Aerospace is a miniscule slice of the pie compared to transportation as a whole, and rocketry is a tiny source compared to commercial aviation. The low-hanging fruit (or high-value targets if you prefer) are more mass transit and more electric vehicles.

      If you can find (or make) an organism that produces or concentrates lithium carbonate, fabulous wealth is in your future.

      1. loupgarous says:

        This French article gives some good starting points for those of us who wish to grow wealthy ploughing the seas for lithium.

        Abstract: 37 species of aquatic mammals, fish, crustacea, annelids, molluscs belonging to cephalopods, gasteropods and lamellibranchs were collected from coastal waters of France: North Sea, English Channel, Atlantic Ocean, Mediterranean Sea, from Greece: Aegian Sea, from North America: Atlantic Ocean and from Japan: Pacific Ocean, Sea of Japan and East China Sea. Microanalyses which were performed on organs and tissues, using secondary ion mass spectrometry, revealed high concentrations of lithium, which is commonly used in human therapy, but is also toxic in low amounts. The retention of this metal by the marine organisms appears as a general phenomenon independent of their biotope and geographical origin; the highest lithium levels were detected in the fish muscles (= edible part).”

        If you just trawl for the fish they mention, perhaps containing a school or two of them behind a vast net in a salt-water bay to reproduce and grow fat, they’ll obligingly concentrate the lithium for you, and all you’d need to do is harvest them periodically, then process the filets for their lithium.

        What’s left could be great fertilizer, or just food for the next generation of fish you’re farming.

      2. loupgarous says:

        The future of rocketry is hydrolox or methalox with IVF, meaning no more hydrazine for RCS and no helium for ullage.

        A lot depends on whether we become so serious about protecting the planet from meteor impact we revive nuclear pulse unit propulsion (the earliest such serious proposal was Project Orion} or invest the necesary resources (orbiting 100 kW nuclear reactors) into VASIMR or other Lorentz ion-drive thrusters.

        The specific impulses of nuclear pulse and plasma ion drives dwarf any chemical or nuclear rocket drive ever made. Nuclear pulse units, unlike comparatively weaker ion drives, also create unprecedentedly high total impulse at the same time. A nuclear pulse drive spacecraft could reach Mars in weeks, not months, and clustered VASIMRs with enough reaction mass and reactor power could make the trip in a few months.

        To avoid creating dozens of extra annual cases of cancer per launch, we’d assemble nuclear pulse ships in space and only fire the nuclear pulse drive once they are well away from Earth (to avoid coupling nuclear detonation X-rays to the ionosphere and creating massive electromagnetic pulse).

        While VASIMR and other ion drives are only practical in-system, using antimatter-catalyzed fusion pulse detonations or relatively small thermonuclear weapon-type pulse units could give us the sort of prolonged, high specific impulse thrust to reach Alpha Centauri in 44 years – the closest we’ll get in the near term to starships.

        Of course, we’ll still need heavy chemical rocket space lift to get these toys out of Earth’s gravity well for assembly, but the true future of space won’t be chemical. It’ll be nuclear.

        1. Chris Phoenix says:

          Space elevators are hard on Earth (but they should be great for Mars) but rotating tethers grabbing suborbital rockets sounds really useful. When they were first proposed we didn’t have the accuracy to fly to the tether, but have you seen SpaceX recently?

    2. John Wayne says:

      I am continually amazed by the chemistry nature has leveraged.

      1. loupgarous says:

        Looking at any of the structures Derek shared today really makes you sympathize with Charles Darwin when he envisioned a Watchmaker. It’s hard to imagine the evolutionary pressures which drove cells to make those compounds.

  2. ex-London Chemist says:

    So how many are real and how many are isolation artefacts? Wasn’t there a paper (quite a few years back) from Brisbane where they saw that quite a few Nat Prods from coral depended on how they were extracted?

  3. A question that came up the other day in a discussion: How many natural products contain triple bonds?

    1. s says:

      I am aware of this one: histrionicotoxin

      1. Cool.

        Though the name sounded like something out of The Onion at first.

    2. NP in my past says:

      All the enedyine compounds like calicheamicin.

    3. antiaromatic says:

      There’s also the Laurencia family of haloether natural products. Almost all of them have an ene-yne motif.

    4. Min says:

      You might find this interesting: recent paper on terminal alkyne natural product biosynthetic pathway

      https://www.nature.com/articles/s41586-019-1020-y.pdf

    5. eub says:

      I think all the ones I know are toxins. Cicutoxin, from water hemlock and friends, has two triple bonds in a row and appears to be gunning for three more. (Totally different from poison hemlock, but also poisonous and also a carrot cousin.)

      What’s the record for conjugated triple bond count? I’ll start the bidding, safynol has 3.
      https://pubchem.ncbi.nlm.nih.gov/compound/Safynol
      Is there an organism that produces unbounded-length polyacetylene?

      Oh, nice article on triple bonds in natural products:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515280/

    6. loupgarous says:

      Any plant that makes cyanide(s): they occur in bitter almonds, the stones and seeds of apricots, apples, and peaches. The Cassava or manioc root from which we get tapioca makes the cyanogenic glucosides, linamarin and lotaustralin, which must be expressed from the root before the meal may be safely eaten.

      The Madagascar bamboo makes cyanide as a deterrent to grazing. The golden bamboo lemur, which eats the bamboo, has developed a high tolerance to cyanide (you see that sort of thing in Western Australian wildlife, which has evolved to tolerate another plant toxin entirely, sodium fluoroacetate, in the indigenous “poison pea”, gastrolobium).

      1. loupgarous says:

        I should have mentioned amygdalin in peach, plum and apricot pits, apple seeds, and bitter almonds as the specific triple-bond containing natural product, on that loosely attached cyanide on one end. Prunasin’s a related compound, also a cyanogenic glucoside found in bitter almonds as well as some Asian cherries and South African “hard pears”.

    7. Druid says:

      Crepenynic acid is the wonderful trivial name for (cis)-octadec-9-en-12-ynoic acid. Glycerides are found in seeds and some hardwoods.

    8. Young Padawan says:

      Another one: Callipeltoside

  4. Sven the Mediocre says:

    Populosone looks like a rolling boulder that’s already crushed one person, with another still running away.

    1. tlp says:

      *me* hitting invisible like button

      1. Carl Bar says:

        Me to. Me to. Also a like for the lion related post below this tangent.

      2. myma says:

        I wish Derek would have made a bracket challenge out of these wierdos. There is always next year. … I think I would have put Telomestatin as the winnah. The random sulfur.

    2. ENES says:

      Hilarious! Reminded me of this classic from P.G. Wodehouse…

      “It was a confusion of ideas between him and one of the lions he was hunting in Kenya that had caused A. B. Spottsworth to make the obituary column. He thought the lion was dead, and the lion thought it wasn’t.”
      Ring for Jeeves (1953)

    3. wannabe chemist says:

      Oh, coffee out the nose hurts….. That’s an absolutely hilarious (and accurate) observation

    4. tim Rowledge says:

      I was just scrolling down to point out that it looks like a rather overwrought logo for an exciting dynamic new something company named Sisyphos Technology . (Imagine dramatic font etc. because I can’t provide one here)

  5. a. nonymaus says:

    10-membered rings? With a ketone? What’s so hard about an oxy-Cope rearrangement of the appropriate divinylcyclohexanol?

    1. MTK says:

      I was thinking about a Grob fragmentation of a decalin derivative.

      At the end of the day it’s more about “Why?” rather than “How?” in terms of why most chemists have never made a 10-membered ring.

    2. Hap says:

      The rearrangement precursor for populosone looks like a PITA. Maybe if you can macrolactonize and then Tebbe, but it didn’t look fun to me.

  6. MrXYZ says:

    Dragocin B reminds me a bit of autoinducer-2, a bacterial quorum-sensing signaling molecule.

    https://en.wikipedia.org/wiki/Autoinducer-2

  7. Min says:

    I was just wondering what are some good sources I can look up some interesting natural products like these?

    1. Dylan says:

      Not necessarily natural products, but Henning Hopf’s “Classics in Hydrocarbon Chemistry” contains veritable bonanza of strange looking molecules, such as cubane, dodecahedrane, tetra-t-butylethylene, “windowpane” (think 4 4-membered rings fused to each other like a window. The latter two of these molecules are yet to succumb to synthesis.

  8. Anonymous says:

    10-membered ring natural products: The Germacranes, e.g., periplanone B and others. (I worked on germacrane syntheses so it was easy to think of them.) There are ring fused examples (epoxied, cyclopropanated, lactone fused, …) but that “rolling boulder” (lol; +1 to Sven) populosone does look weird.

    Fragile looking compounds like dragocin B make me want to follow the isolation details very carefully to see if it is natural product or a preparative artifact.

    (Asking again for Derek and sciencemag.org to make “In the Pipeline” using forum software rather than blogging software. It would be easier to search the valuable archive of old posts, easier to give “likes”, etc.. Derek would still control the creation of New Topics threads, etc.. And maybe add a structure drawing applet so repliers could include a structure, when appropriate. And, and, and …)

  9. Emjeff says:

    Re that Dragocin B compound, is the carbon with the oxygen and Cl attached to it positively charged? I would guess that the electron density around that carbon is near zero.

  10. Tomas Pluskal says:

    My favorite bizarre molecule: https://en.wikipedia.org/wiki/Calicheamicin

    1. eyesoars says:

      What is the strain on that yne-ene-yne section? It looks like a booby-trap, and apparently acts that way too.

      1. Hap says:

        There’s worse – there’s nine-membered enynes (https://en.wikipedia.org/wiki/Neocarzinostatin) that Myers’s group (and others) prepared – they’re mostly not stable unless there’s a chaperone around, but they still exist.

  11. BakedAlaskan says:

    I liked this recent one. Has some interesting features in there.

    https://pubs.acs.org/doi/pdf/10.1021/jacs.8b11403

  12. Ken says:

    I’m reminded of a line from Michael Pollan’s The Botany of Desire – something like “plants may be thought of as small chemical warfare factories”.

  13. Handles says:

    Check out the strain on this one from this week’s J. Nat. Prod.:
    https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00232
    Need to find my modelling kit I so I can try to build it.

    1. Handles says:

      Actually, its not as bad as I thought. My dodgy minimisation in Chem3D says that that lactone is “only” ~cyclobutane levels of strain (25 kcal/mol). Still wouldn’t want to try to isolate it without it popping open.

      1. anon the II says:

        Whenever I see a funky molecule and wonder how it could be, I whip out Avogadro (https://avogadro.cc/), built the molecule and minimize it with the MMFf94s force field. Some nice aspects of Avogadro are that it’s free, runs on a Mac (and PC) and you can grab atoms and jerk them around while the minimization is happening. That last feature allows you to get the stereo-chem right if your original drawing is wrong and you can explore some conformational options in real time. Did I mention that it’s free?

  14. Pernickety thiaza-heterocyclist says:

    Telomestatin bears a thiazoline ring…..just sayin’ ;P

  15. Simon Auclair says:

    A woman needs a man like a fish needs a heterocycle.

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