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January 27, 2010
Enzymes and Fluorines
It hit me, one day during my graduate career, that I was spending my nights, days, weekends, and holidays trying to make a natural product, while the bacterium that produced the thing in the first place was sitting around in the dirt of a Texas golf course, making the molecule at ambient temperature in water and managing to perform all its other pressing business at the same time. This put me in my place. I've respected biosynthesis ever since.
But there are some areas where we humans can still outproduce the small-and-slimies, and one of those is in organofluorine compounds. Fluorine's a wonderful element to use in medicinal chemistry, since it alters the electronic properties of your molecule without changing its shape (or adding much weight), and the C-F bond is metabolically inert. But those very properties can make fluorination a tricky business. If you can displace a leaving group with fluoride ion to get your compound, then good for you. Too often, though, those charges are the wrong way around, and electrophilic fluorination is the only solution. There are heaps of different ways to do this in the literature, which is a sign to the experienced chemist that there are no general methods to be had. (That's one of my Laws of the Lab, actually). The reagents needed for these transformations start with a few in the Easily Dealt With category, wind entertainingly through the Rather Unusual, and rapidly pile up over at the Truly Alarming end.
But at least we can get some things to work. The natural products with fluorine in them can be counted on the fingers. A fluorinase enzyme has been isolated which does the biotransformation on
4-fluorothreonine S-adenosyl methionine (using fluoride ion, naturally - if an enzyme is ever discovered that uses electrophilic F-plus as an intermediate, I will stand at attention and salute it). And now comes word that this has been successfully engineered into another bacterial species, and used to produce a fluorine analog of that bacterium's usual organochlorine natural product.
It isn't pretty, but it does work. One big problem is that the fluoride ion the enzyme needs is toxic to the rest of the organism, so you can't push this system too hard. But the interest in this sort of transformation is too high (and the potential stakes too lucrative) to keep it from being obscure forever. Bring on the fluorinating enzymes!
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