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The Enantioselective Ugi

This is a remarkable result: a group from Shenzhen reports an enantioselective Ugi reaction. If you’re among the majority of the human race that doesn’t know what an Ugi reaction is to start with, it’s probably the best-known of a rather rare category, a four-component reaction. You take an aldehyde (ketones can work, too), an acid, an amine, and an isonitrile and get out an alpha-acylamino amide that incorporates the side chains of all four reactants. Now, if you mix up four completely different types of reactive compounds and let them rip, you’re generally going to come back to a mixture that resembles chewing gum, used lawnmower oil, or some combination thereof. But the Ugi’s mechanism sends it down an orderly path pretty well, and the resulting products are perfectly reasonable peptide mimetics (as well as containing a motif found in natural products). They don’t have to be linear, either: cyclic structures of all sorts can be generated as well. (There’s a related three-component reaction, the Passerini, and its products can sometimes be contaminants in an Ugi).

That led to a period of Ugi abuse some years back, during the first combinatorial chemistry craze. The temptation of four different groups being varied in one pot, and especially ones available from commercial collections as deep as aldehydes, primary amines, and carboxylic acids are, was too much to resist and vast numbers of these things were cranked out. (Isocyanides are less well represented commercially, partly because those other categories are titanically huge and partly because isocyanides themselves are pretty intolerable to be around). You could make millions of Ugi products (in theory!) just based on the variety of starting materials found in any drug company’s reagent collection, had you large enough quantities to start with and a solid deal worked out with Satan that required you to keep running the same reaction for the rest of your life or be sent to Hell. Not that you’d be able to tell the difference after several decades of nothing but Ugis, but the same would apply to any reaction, which is why high-throughput robotic synthesis can be such an appealing idea!

But note that R1 group in the middle of the structure: that’s a chiral center, and mechanistically you can’t carry it in there from the starting materials, because it’s on the carbonyl component. You’re going to get a racemate, and that’s just what people have mostly gotten over the years, despite many attempts to find some sort of additive or catalyst that would give you a single enantiomer. There’s been progress, as detailed in this review from earlier in 2018, but no general solution had been found.

Perhaps one has been found now. Chiral phosphoric acids have been investigated for enantioselective addition to imines, and that’s just what the Ugi needs. A delicate coordination structure forms that brings everything together just right, accelerating the catalyzed reaction substantially over the background racemic one. Several groups have been working on this exact approach (including the ones that published that review above), and it appears that the Shenzhen group (at the Southern University of Science and Technology) has gotten the idea all the way through. As you’ll see if you read the paper, it took a lot of tweaking, and you still have to vary conditions based on whether you’re using an aromatic or aliphatic aldehyde, among other things. But the enantiomeric excesses reported are quite good overall, and once optimized, the reactions seem to tolerate a wide range of amines, acids, and isocyanides. An example is shown working at the gram scale as well, so this looks like the way to go.

6 comments on “The Enantioselective Ugi”

  1. A Nonny Mouse says:

    Can’t find the paper reference….

    1. Derek Lowe says:

      As usual, with me! Fixed now. . .

  2. Project Osprey says:

    I can’t get into the paper but what you’re describing sounds like an extension of the enantioselective Kabachnik–Fields reaction, which has been long known

  3. Project Osprey says:

    No not… sorry I’ve not have enough yet caffeine today

  4. Magrinho says:

    “a period of Ugi abuse” That’s good!

    The Passerini just couldn’t get me there anymore. I woke up one morning on the floor of a lab full of primary amines and cyanuric chloride and I knew I had to change.

  5. Surfactrant says:

    Oh the nostalgia… it burns!
    I loved doing Ugi’s back in the day…so robust!
    Even met the man himself once…it was a fun dinner.

    I swear i used to get whiffs of isonitriles while taking a decompression stroll in the university arboretum…

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