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Hindered Ethers Made Easier

Since I mentioned a new Mitsunobu-type reaction yesterday, I should note that a new route to hindered ethers has come out this summer from the Baran group at Scripps. Here’s the ChemRxiv version, and here’s the Nature paper that just appeared. And there are more details at the group’s blog here. It’s an electrochemical reaction that involves decarboxylation to give very reactive carbocations that are then trapped by oxygen nucleophiles. You can make ethers, or use the reaction as a way to prepare alcohols if you just let water trap the cation, and if you really are into it, you can even trap with things like fluoride (albeit in lower yields).

These kinds of hindered products are totally unavailable through Mitsunobu chemistry, or through the classic Williamson ether synthesis, or basically anything that involves Sn2 nucleophilic attack. And the paper shows some dramatic examples of this, with compounds that were either unknown or only prepared by all-the-way-around-the-barn methods that can now be made directly. If you read the paper, you’ll see that this took a lot of experimentation. There are numerous variables and side reactions, and you cannot figure out how to solve them from first principles. The Kolbe electrolysis reaction is the 19th-century forerunner (1847!) to this work and the related Hofer-Moest reaction (1902) is an even more direct ancestor. But that uses the alcohol partner as the solvent, which is not a practical solution:

It became immediately apparent that limiting the amount of alcohol posed several considerable challenges: the decomposition of the carbocation due to the low nucleophilicity of alcohols; the competitive trapping of the carbocation by water; the consumption of alcohols by anodic oxidation; and the necessity of an external electron-acceptor in order to balance electrons. Figure 1c summarizes the results of around 1,000 experiments (see Supplementary Information for an extensive sampling) that were undertaken in order to solve these problems.

Adjusting the solvent, the electron acceptor, the anode material, and the addition of small amounts of base were all crucial, but the resulting reaction looks pretty robust (and naturally can be realized with the Baran-developed ElectraSyn device). Olefins, esters, acetals, Boc- and Cbz-amines, heterocycles, alkyl and aryl halides, and boronic esters are all compatible with the conditions. As the blog post linked above notes, though, you’ll do best if your acid (and the resulting carbocation) is tertiary, given the well-known stability order of carbocations.

So this could open up a number of compounds that normally you wouldn’t even think about, because ether synthesis is just synonymous in most synthetic chemists’ minds with nucleophilic displacement, and hindered things Just Don’t Work. We’ve all pushed the boundaries of such reactions. When I first started out in the lab in grad school, I had some tetrahydropyran derivatives to make, and a suggested synthetic route had been mapped out for me. I plunged in, but pretty quickly came up against the step to form the ring, which was an arrow with “Mitsunobu” written across the top. My first Mitsunobu! And it was hopeless; the starting material was just too hindered, as I shortly realized. I’ve told the story of how I got around that problem here, which was a valuable lesson in taking people’s word for stuff.

I would assume that intramolecular variants of this new electrochemical route would be a nice way to prepare crowded cyclic ethers as well. I’m always glad to see things come up that demolish the classic synthetic routes and disconnections that we all have in our heads!

8 comments on “Hindered Ethers Made Easier”

  1. Hap says:

    I remember trying a Mitsunobu on an eight-membered ring in grad school (cis-5-benzyloxy-1-cyclooctanol) and remarkably enough not getting much other than cyclooctenes. I didn’t really know what was going on, but they are lots of ways to find crap that this might help.

  2. organic chemist says:

    The one thing I don’t like is the way it’s sold:
    “Farewell Williamson ether synthesis”

    Well, no. I would argue it’s mostly orthogonal to the Williamson ether synthesis. Baran can’t do secondary (unless very activated) or primary electrophiles, Williamson can obviously not do tertiary.

    That aside, the yields are pretty low across the board, no? 9 out of over 60 examples are 70% yield and above, maybe 15 or so are above 60% yield. For the most part, it’s in the 30-50% range.
    With 1.5 equiv of AgPF6 and 3 equiv of nucleophile, there’s still a lot of room for improvement in my opinion.

    So while this is really cool chemistry, I don’t see us saying farewell to good ol’ Williamson anytime soon.

    1. Derek Lowe says:

      Exactly – this and the Williamson would seem to overlap very little.

      1. milkshake says:

        this is a way of oxidizing tertiary radicals to carbocations under neutral and low coordinating conditions. I think the best comparison would be with thermolysis of tertiary or benzylic triflates made in situ from tertiary alcohol with Tf2O and 2,6-di-tBu-pyridine at low temperature and warmed up to R.T.

    2. anon says:

      In sophomore organic chemistry terms, it’s SN2 and SN1 chemistry. Both (and things in between) are useful.

      Classic Phil overhyping up his work, when he doesn’t need to.

    3. Chacao says:

      Given the degree of difficulty of the transformations, the yield are very good, especially given the binary nature of MedChem yields (enough to go on, not enough). I prefer an honestly reported, reproducible yield than…… you know.
      I guess we’ll see how reliable the method is as people start trying it

    4. Mad Chemist says:

      Agreed. Even if this were to work with primary electrophiles, I would still prefer the Williamson because its much simpler and give high yields.

  3. matt says:

    Pardon the interruption of interesting new chemistry…no comment yet on the Nature paper generating all the “resetting your biological age” headlines? To me, the interesting thing is the way the idea has an obvious route to serious scientific testing and then (reputable) commercialization (i.e., FDA approval for immune-related conditions). That is generally lacking (sometimes by design, but even when not as in the metformin studies) in most “fountain of youth” or “Methuselah Project” ideas.

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