Well, people have been searching for a reaction like this one for quite a while now: that link describes a catalytic Mitsunobu-like reaction, and the original has always been a transformation that synthetic organic chemists groan about but use anyway. It’s a way of substituting an OH group in one pot with what should be clean stereochemical inversion, and you can use a variety of nucleophiles. One common use is inverting a stereocenter by forming an ester product – hydrolyze it and you’ve got the alcohol back in the opposite stereochemistry. And it’s also used a lot to make ethers, particularly for intramolecular ring-forming ones or acyclic aryl ether formation. It’s been around for decades, it’s all over the literature, and you’d have to search for a bit to find a working synthetic chemist who’s never run one. So why all the grumbling?
Because it’s a mess. The classic Mitsunobu uses stoichiometric diethylazodicarboxylate and stoichiometric triphenylphophine, and the latter ends up as triphenylphosphine oxide. That last conversion is the thermodynamic “battery” that runs a number of organic chemistry transformations (such as the original Wittig reaction), but no one is happy about dealing with all the phosphine oxide when it’s purification time. Sometimes you can extract your product out or precipitate the TPPO out and get away clean, but other times it’s a slog. And you never feel like you’re doing elegant chemistry when you chew up so much reagent (both the DEAD and the TPP) to do something like flip a single OH group. If “atom efficiency” is your thing, you have to avert your eyes from the Mitsunobu.
I would not like to count the variations that have been proposed over the years, but most of these have involved alternatives to the azo reagent and still produce a phosphine oxide. Polymer-supported reagents, more water-soluble variants, all sorts of things have appeared. But getting both catalytic has been a tall order, because the DEAD gets reduced in the reaction while the TPP gets oxidized, so you’re going in two directions at once if you want to cycle those around. This new paper, though, has an ingenious solution shown at right. You start with the phosphorus already in the +5 oxidation state and go through a reactive cyclic intermediate that gets regenerated. So the reaction is catalytic in both directions (the oxidation and the reduction) and throws off only an equivalent of water as a byproduct. Pretty slick!
This also lets you do esterification on alcohols that are sensitive to the more common methods, and the pre-oxidized phosphine lets you get away with substrates that have groups (alkyl bromides/iodides, azides) that would reaction with triphenylphosphine itself. The authors (Univ. of Nottingham and GSK) do a thorough mechanistic investigation into the reaction, and they note that this system might also be applied to other phosphine/phosphine oxide driven reactions.
If this works as well as advertised – and I see no reason up front to think it doesn’t – then I would expect this to almost entirely replace the original Mitsunobu, which has had an over fifty-year run as a synthetic chemistry workhorse. It will also kill off the market for DEAD and similar reagents; if there were a good single-supplier play for azodicarboxylates I would have gone short their stock immediately on reading this paper. Congratulations to the authors!