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One Sugar Turns Into Another

As someone who used a lot of carbohydrates as chiral pool starting materials in grad school, I regard this paper as the next thing to witchcraft. Even folks without carbohydrate experience appreciate readily that there are sugars that you hear about all the time (such as glucose, mannose, and galactose) and some that you hardly ever hear about at all (such as allose, gulose, and talose). That’s not even getting into the deoxys and the aminos and all the rest of the derivatives; those guys are straight-up members of the sugar club, but they’re just rare in nature (and correspondingly expensive in commerce).

Emil Fischer famously synthesized his way through the carbohydrates in the early days of the field and confirmed the stereochemical relationships between them, a tour de force that still ranks as one of the truly impressive feats of organic chemistry. So it’s not like you can’t synthesize all sorts of rare carbohydrates, but it can be quite painful and expensive to do so. Carbohydrate chemistry has long been The Land of Protecting Groups, and for good reason, since there’s a hydroxyl group coming off of nearly every carbon that can host one. Now it’s true that each of those hydroxyls on each different sugar backbone has its own personality (hostile, in many cases), and there are whole lists of odd little reactions that will open up or protect one particular one (or two adjacent ones). Carbohydrate chemistry is like steroid chemistry in that regard – these crowded ring systems have all sorts of reactions that you wouldn’t think you could do but you can, and a similar list of things that look perfectly plausible on paper but just don’t work.

So the paper mentioned above, from the Wendlandt group at MIT, is particularly interesting because it’s working on completely unprotected sugar systems. It features a hydrogen abstraction/donation mechanism (through photoredox catalysis) that basically just reaches in and epimerizes free hydroxy groups. There have been several other papers in recent years that target reactions such as C-H alkylation on such systems, with the shared goal of getting out of the aforementioned Protecting Group Land. This paper shares some similarities to those earlier ones – for example, seeing reactions at the C-3 hydroxy more often than not.

The authors freely admit that reasons for the selectivity of the reaction are not clear. From what I can see, the alpha-methyl glycosides tend to epimerize the C3 OH, and the beta-methyl ones tend to react at C2. Free sugars (OH at the anomeric position) react as well, albeit in lower yields. 2-deoxy sugars can be epimerized at their 3 position, which is something that basically you just haven’t been able to do. Even disaccharides like sucrose or raffinose have single OH groups isomerized, and the reaction can also be done on nucleosides and C-glycosides as well. Yields vary, but as I said earlier, I’m just amazed that this can be done at all. Figuring out the reasons for the selectivities, which clearly seem to be under kinetic control and not thermodynamic, and seeing if other OH groups can be dragged into participating will be something to watch for. Rare sugars might end up not being quite as rare. . .

 

23 comments on “One Sugar Turns Into Another”

  1. luysii says:

    I never saw this anywhere (perhaps because it’s obvious), but the reason glucose is used by living organisms, is that all the (bulky compared to hydrogen) hydroxyl groups can be equatorial. Also true of the enantiomer.

  2. Jb says:

    Izumoring has been around since the early/mid 2000s that was a rational way to reach all known hexoses. I guess the advantage would be if there are any yield improvements or shortening in the number of steps.

    https://www.sciencedirect.com/science/article/pii/S1389172304701735

    Anyways, I spent a good deal of time doing carbohydrate chemistry as well. Talk about a nightmare. It’s gotta be the hardest field to work in for a synthetic organic chemist. Most modern organic transformations don’t work. And on top of that, purifications of highly polar molecules you can’t see via uv is always a blast.

    1. Pedant says:

      We won’t be in the mid 2000s for about 25 years! Don’t rush!

      1. Another Pedant says:

        You could argue it’s about 400 years…

  3. John Wayne says:

    “Now it’s true that each of those hydroxyls on each different sugar backbone has its own personality (hostile, in many cases), …”

    The last phrase there made me laugh out loud (open office space, etc.)

  4. Dr.Wood says:

    To add to the fun, remember that sugars in water each exist in a range of different structures, and the ratio of one structure to the next is different for each sugar. Just in case you were not having enough fun yet, you aren’t dealing with 1 structure, you are dealing with 5.

    1. Derek Lowe says:

      How true. And those ratios vary, of course, by concentration and temperature, and when you derivatize said sugar you can, of course, get products that come from any of those equilibrating structure, such as the alpha- or beta-glycosides of glucose, the alpha-glucofuranose form (as in “diacetone glucose”), or something from the open-chain (like the osazone). It’s a party.

    2. Anonymous says:

      Dr.Wood: “the ratio of one structure to the next is different for each,” sometimes from each research group describing their work! (And not just sugars: e.g., lysergic / isolysergic acid ratio; etc.) I had one of those, with many characterizable equilibrating isomers. I reported A:B:…F that was different from the other groups that were all different from each other. As Derek points out, small effects can produce these noticeable differences.

      1. Dr. Wood says:

        Agreed!! push your pH or ionic strength around and I would not be at all surprised if those equilibria shifted. Temperature can probably push it around too. Everything blasted matters, and woe to those who forget it!

  5. Josh says:

    The paper is very interesting, however the SI reveals some of the major issues of all work with unprotected sugars. In order to purify the products you have to globally acetylated and then deacetylate the sugars, which adds two hidden steps.

    Furthermore, although there are some examples of silyl protected alcohols, the chemistry does not tolerate benzyl ether’s (presumable due to the presence of weak benzylic C-H bonds), which are by far the protecting group of choice for synthetic carbohydrate chemists.

    Finally in the context of synthetic carbohydrate chemistry, there are already several reliable ways to effectively carry out this transformation on protected sugars including oxidation of an alcohol followed by reduction with a bulky hydride source, as well as triflation and SN2 inversion using a nitrite salt (termed a Latrell-Dax inversion)

  6. NoMorePGs! says:

    This is a great point: modern organic synthesis evolved out of work on greaseball molecules. Most glycochemistry focuses on trying to convert sugars into a more palatable form for subsequent manipulations/purification, masking their reactivity and thus requiring harsh reaction conditions, which in turn makes controlling selectivity difficult.

    Methods like this push the envelope to stop treating sugars like polyketides. We need new reactions as well as new analytical/chromatographic techniques to enable the synthesis and isolation of carbohydrates. I think this work presents a fantastic step forward and I look forward to continued work in the area!

    Something to consider: when you protect a glucose with benzyl groups, your substrate becomes 2/3 protecting groups by mol wt. Is that still a sugar?

    1. anon says:

      You’re 2/3 H2O, but we don’t call you a sack of water.

    2. Student says:

      Why does adding PGs mean that you subsequently use harsh conditions? In peptide chemistry you also use a lot of PGs and very mild conditions because your substrates stay fragile (especially towards epimerization), just less reactive.

  7. NoMorePGs! says:

    It’s actually remarkably different from peptide chemistry! The intrinsic reactivity of a sugar hydroxyl has been shown to be dramatically diminished when neighboring hydroxyls are protected (Codée, Jacobsen, and others). The electronics and sterics of these protecting groups influence both the hydroxyl group’s reactivity and the anomeric selectivity of glycosylation reactions.

    The harsh conditions are generally necessary to add a hindered, protonated hydroxyl group into an anomeric carbon. Much of glycosylation chemistry relies of activation that group with strongly oxidizing or Lewis acidic conditions to generate a sufficiently reactive species for displacement to occur.

    This contrasts quite a bit from peptide chemistry where a carboxylate activates a leaving group and is displaced by an amine, which is orders of magnitude more nucleophilic compared to a C4 hydroxyl of a 1,2,3,6 tetrabenzyl glucose.

  8. Arteminsinin says:

    Can somebody here tell me whether there is any successful case where a drug candidate is glycosylated and turned into a more soluble prodrug?

    1. Algirdas Velyvis says:

      I don’t know of any man-made drugs where this is taken advantage of (not in med chem myself), but this is thought to be a major reason why plants produce all those nasty glycosides: glycoside form is a pro-cide. So, some poor vegetarian schmuck ingests dhurrin, dhurrin gets hydrolyzed into a sugar and cyanohydrin, which in turn gives you p-hydroxybenzalhedyde + HCN. Bang! One vegetarian fewer.

      Interestingly, there was a paper a few years ago (10.1038/ncomms9525) demonstrating an exception to this rule: a glycoside toxic to tobacco hornworm is detoxified by glycolysis.

      1. Ted says:

        Hi:

        My thoughts are on the same lines. A major focus in the mycotoxin community has been developing methods to detect toxic fungal metabolites that undergo modification by their plant hosts. We have regulatory limits for various aflatoxins, fumonisin, deoxynivalenol, etc… in our food supply, but we often don’t detect the exact same toxin when it is coming in as a toxin~glycoside (for example). After you eat it, and the toxin is liberated in your intestinal tract, you probably don’t care whether you ingested the pro-drug version instead of the real McCoy. The area is covered under the rubric of ‘masked mycotoxins.’

        -t

  9. Anon says:

    https://www.bbc.com/news/health-51182451

    Typical BBC hype, or real potential?

    1. loupgarous says:

      Two tips to translating any popular science article (not just BBC, but Wired, Scientific American), et cetera:

      1 – The BBC screwed up in saying in their lede:

      A newly-discovered part of our immune system could be harnessed to treat all cancers, say scientists

      .Translation:

      This is why we’re journalists, and not oncologists. This is hype, and potentially could raise hopes in badly ill people. Not all cancers look or act alike, and we don’t know if ‘all cancers’ will respond to this treatment.”

      2 – “Experts said that although the work was still at an early stage, it was very exciting.”

      Translation:

      “we got it to work in the lab in vitro and in some animal models. Most “cures” for Alzheimer’s disease worked great in mice. God knows how CRISPRing a T-cell to include the sequence we are excited about works in man.”

      The Beeb was being truthful, but economical, perhaps, in how they told the truth. But it wasn’t quite hype.

      3 – “What do the experts say?”

      Translation:

      Actually, this part of the article was absolutely truthful. Each of the statements made by the other researchers whose opinions they rounded up was carefully not promising anything.

      It’s too early yet to say this new T-cell will work in people or that it won’t have unanticipated bad effects in the human body. That’s what the people interviewed from other labs said. Good for them.

      Bonus good thing from two of the experts:

      “Lucia Mori and Gennaro De Libero, from University of Basel in Switzerland, said the research had “great potential” but was at too early a stage to say it would work in all cancers.”

      .This requires no translation, either. The BBC screwed up in saying in their lede:

      A newly-discovered part of our immune system could be harnessed to treat all cancers, say scientists

      .That IS hype, and could raise hopes in badly ill people. The idea of something that looks at all human cell surfaces and only acts to destroy the cancerous ones remains to be tested.

      Even if it does work, cancer cells mutate much more rapidly than normal cells. If the ones that can be killed by this new T-cell work, we don’t know if cancer cells can mutate to work around the T-cell attack or not.

  10. Noni Mausa says:

    Not being a chemist, I’m curious about those “hostile sugars.” Could you guys fill me in on a few?

    1. Derek Lowe says:

      It’s more like particular OH groups. There are famous examples where you’d think that you could do a certain type of reaction on some OH group (oxidation, conversion to a leaving group and displacement, others) and it just flat out won’t work. This is often because it’s in some position where the other oxygens on the sugar are placed to interfere with or change that one’s reactivity. Meanwhile, an isomeric sugar with the offending OH group flipped to the other stereochemisty often works just fine but the one you want to use will just sit there and laugh at you. These “stereoelectronic effects” are known in all sorts of organic chemistry reactions, but the dense nearly-every-carbon-functionalized structure of sugar molecules guarantees that you’ll see plenty of this stuff.

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