Chloramphenicol base

 

I have been doing some asymmetric hydrogenations recently. The pieces that I was making were carboxylic acids and since the highest optical purity that I could get from my system was about 90%ee and the product couldn’t be enriched by a simple recrystallization, I needed to make a salt  – preferably with some optically pure amine – to bring the material up to 98-99% ee.  I got quite lucky with chloramphenicol base: the salt enrichment in a single recrystallization proceeded with high recovery. 

I also tried few other chiral amines, norephedrine worked but it was not very efficient (with the salt being too soluble). And norephedrine is rather expensive and it is on the controlled precursor list – its delivery got halted for nearly a week by the bureaucracy and eventually we had to fax a statement to the supplier, declaring that we are not making a dope. 

This got me to realize that unlike with the chiral pool of acids, there is only a limited choice of inexpensive optically pure amines that one can buy both enantiomers of (a typical problem with many alkaloids and other natural-product derived amines). Chloramphenicol is a generic antibiotic made by old-fashioned racemic synthesis and resolution hence both enantiomers are available. And not every amine is likely to provide a nice crystalline salt; what probably makes chloramphenicol base effective is the combination of para-subst nitrophenyl group and the two hydroxy groups that contribute to ordered interactions in the crystal structure. 

Chloramphenicol base has been used as a resolving agent in industry: Roussel Uclaf, the company that commercionalized a large-scale production of chloramphenicol many years ago, is using the base as a resolving agent for racemic trans chrysantemic acid – a precursor for making synthetic pyrethroid insecticides such as Deltamethrin. The resolution takes place very early in the sequence. Given that pyrethroids are made on ton scale, the availability of the optically pure amine needs to be pretty good.

The actual resolution of racemic chloramphenicol base is noteworthy: Chloramphenicol base is among the rare (1-2%) compounds that crystallize as a conglomerate of optically pure crystals. This means that it can be resolved by selective crystallization based on seeding with one and then the other enantiomer. In reality the process is somewhat tricky – one has to work under carefully controlled conditions and use a massive quantity of the enantiomerically-pure seeding material to have a fast growth, and stop the crystallization very early to ensure that the other enantiomer keeps in the super-saturated solution. But this sort of process is doable in a chemical plant and “resolving stuff with nothing” helps to produce the optically pure material cheaply .