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.
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!