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December 12, 2013
Tiny Details, Not So Tiny
Chemjobber has a good post on a set of papers from Pfizer's process chemists. They're preparing filibuvir, and a key step along the way is a Dieckmann cyclization. Well, no problem, say the folks who've never run one of these things - just hit the diester compound with some base, right?
But which base? The example in CJ's post is a good one to show how much variation you can get in these things. As it turned out, LiHMDS was the base of choice, much better than NaHMDS or KHMDS. Potassium t-butoxide was just awful. But the hexamethyldisilazide was even much better than LDA, and those two are normally pretty close. But there were even finer distinctions to be made: it turned out that the reaction was (reproducibly) slightly better or slightly worse with LiHMDS from different suppliers. The difference came down to two processes used to prepare the reagent - via n-BuLi or via lithium metal, and the Pfizer team still isn't sure what the difference is that's making all the difference (see the link for more details).
That's pure, 100-proof process chemistry for you, chasing down these details. It's a good thing for people who don't do that kind of work at all, though, to read some of these papers, because it'll give you an appreciation of variables that otherwise you might not think of at all. When you get down to it, a lot of our reactions are balancing on some fairly wobbly tightropes strung across the energy-surface landscape, and it doesn't take much of a push to send them sliding off in different directions. Choice of cation, of Lewis acid, of solvent, of temperature, order of addition - these and other factors can be thermodynamic and kinetic game-changers. We really don't know too many details about what happens in our reaction flasks.
And a brief med-chem note, for context: filibuvir, into which all this work was put, was dropped from development earlier this year. Sometimes you have to do all the work just to get to the point where you can drop these things - that's the business.
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