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Chemical Biology

A New Amine Reaction – In Fact, Several

I’ve been meaning to write about this new amine-substitution chemistry from the Baran group at Scripps, in collaboration with Pfizer’s labs in La Jolla. It’s a technique that they’re calling “strain-release amination”, because it’s being applied to strained small-ring systems like [1.1.1]bicyclopentaneamine. These are useful systems (and Pfizer’s been exploring them for some time now), but they’re a pain to work with, synthetically. Indeed, the paper mentions that Pfizer had to abandon a clinical candidate that had such an amine in it because of sheer synthetic difficulty on scale.

Baran amination

This new route involves in situ generation of the corresponding propellane (which has an extremely strained “axis” bond in the middle of its three cyclopropyls) and reacting that with a dibenzylamine magnesium salt. This reacts quite cleanly to give the desired bicycloamine, and the benzyl groups are then cleaved off easily. Should you find yourself making a series of these beasts, it’s also possible to make stock solutions of the propellane itself and keep them at -20 or -78 degrees, where they’re stable on a time scale of weeks to months, respectively. You don’t have to make the primary amine from it if you don’t want to, though – other amine nucleophiles work as well, so if you can form the magnesium salt, you can bring in a piperidine, piperazine, or whatever you like directly. The paper demonstrates this reaction on a range of substrates, including some last-step-functionalization of drug scaffolds.

The same idea is then used to append a 3-azetidinyl group onto your amine of choice, using the in situ generated bicycloamine (which is also ready to break that strained bond in the middle), and a similar sulfonyl-substituted bicyclobutane to add an instant N-cyclobutyl. A range of examples are demonstrated for each, and (as they authors surmise) you could easily imagine this sort of bond-breaking approach being used to put on other small-ring substituents. As an aside, I have to congratulate Baran and his co-authors for resisting the temptation to turn this paper into at least three others, any of which would have been more interesting than most of the stand-alone papers I see.

But wait, there’s more, as they used to say on the old cable TV ads. They go on to show that exposing a model peptide to their most reactive cyclobutyl-ating reagent selectively labels its Cys residue, as well it might, and is much more selective than maleimide. This is basically an entirely new class of “click” reaction, a la Sharpless, and should find a number of uses. In fact, it wouldn’t surprise me if that last couple of paragraphs of this paper turn out to get even more use than the rest of it in the years to come. Very nice stuff, and a pleasure to read!

11 comments on “A New Amine Reaction – In Fact, Several”

  1. Sofia says:

    I remember seeing this paper crop up a while back and the click chemistry you allude to in the closing statement here made me giddy with delight. In the absence of sulfur nucleophiles on peptide or peptoid fragments I’d be curious to see what sort of amine selectivity you could achieve with these labeling reagents. They are fairly small and uniquely stable – so I imagine the results of some competitive reactions on the same residue might yield surprisingly results.

  2. Mose says:

    This is mighty impressive. The SI took 20 minutes to download but was worth it. Never seen anything like this.

  3. bad wolf says:

    “As an aside, I have to congratulate Baran and his co-authors for resisting the temptation to turn this paper into at least three others,

    Congratulate them? Isn’t that SOP for glamour mags–make you put in several papers’ worth of results?

  4. anon says:

    Nice paper. I am sorry but these types of studies prove that industry doesn’t need R&D labs. Give some academic lab enough money, they’ll save you a lot of trouble.

    1. me says:

      lol perhaps. My take on it would be that Baran’s lab is not just ‘some’ academic lab.

      My other take on it would be that, while this is all useful stuff, someone still has to translate it into drug leads. Something that Baran himself is not specialist in.

    2. Albert says:

      Right and if you have no industrial R&D then 80-90% of those academic labs will cease to exist. No jobs so also no or very few PhD students/postdocs. As an industrial process chemist I can tell you we also do a lot of cool stuff. Of course not everything is published, but some things are. Just as an example this paper from Boehringer Ingelheim is one of the most useful ones I’ve red last year: http://pubs.acs.org/doi/abs/10.1021/jacs.5b06136

      1. barney featherson says:

        Albert
        Nice to hear from a process chemist-the most underrated or should I say underappreciated chemists out there. Agree with your comments. Quiz time: Do you know who was the first guy to make the [1.1.1.] propellane (circa 1980)? Hint: he was my labmate. At first we looked at the NMR and thought it was acetone.

  5. Algirdas says:

    I find the part about maleimide lacking specificity strange. Typically one uses N-modified maleimide to put some modification onto cysteine side chains of protein – in aqueous solution under mild conditions. I have never looked very carefully for side products, but one time that I’ve checked MS of the product, reaction was complete in 1 hour, single-cys protein was quantitatively converted into an adduct, and no multiply-labeled side products were apparent (using 5x excess of maleimide).

    Their approach in this paper, is to pickle the peptide with maleimide in presence of 0.13 M K2CO3 for up to 24 hours. HPLC is showing some reaction byproducts (i.e. undesirable products with cysteine-free peptide) after 1 hour already. I guess now I know what conditions to avoid for maleimide labeling (should I ever want to put my proteins in DMF-water mixtures to begin with).

    (An unrelated aside: HPLC traces in fig. S59 in the supporting info shows only a single peak for product, while reaction is expected to generate a pair of diastereomers. The HPLC column seems to have fairly good resolution, so I’m assuming diastereomers will not coelute. This seems to imply that diastereomeric excess is very high, but perhaps this is to be expected for 1,3-disubstituted cyclobutyl reactions.)

    1. LiqC says:

      Both this paper and Buchwald’s Nature paper compare their new reagents to prior thiol-labeling agents under very artificial conditions. S:N selectivity of maleimides is about 10,000 for pure nucleophiles (deprotonated RS- vs RNH2). Under their conditions the maleimide reaction with thiols is complete in a fraction of a second, leaving plenty of time for the reaction with amines.

      N-(Beta-aminoethyl)maleimide trifluoroacetate, a reagent used to convert R-COOH to R-maleimide, is a testament that maleimides aren’t that reactive towards amines.

  6. svb reddy says:

    Really worth full material, thanks a lot Mr DL. and congrats o Dr Baran and co.,

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