Content area
Full text
Patrick J. Walsh,* Diane K. Smith,* and Chris Costello
An important property of biological systems is their ability to differentiate between enantiomers. The interactions of enantiomers with organisms are diastereomeric owing to the chiral nature of molecules in cells. Therefore, the enantiomers are recognized by the organism as different molecules that elicit different physiological responses. Perhaps the most dramatic and well-known example of this effect is thalidomide, which contains one chiral center (1). Thalidomide was originally sold as a racemic mixture. Whereas one of the enantiomers is a sedative and mild hypnotic, the other is teratogenic and causes stunted limb development in utero, as occurred in Europe in the late 1950s when the drug was taken during the first trimester of pregnancy. To prevent thalidomide-type tragedies, the FDA is now requiring testing and marketing of single-enantiomer drugs. In response, synthetic chemists are developing new methodologies to produce chiral compounds as pure enantiomers (2). The move to manufacture medications in optically pure form is also motivated by economics. It has been predicted that the market for synthetic chiral drugs produced as single enantiomers will reach 40 billion dollars by 1997 (3) and that 34% of all medications will be synthesized as single enantiomers by the year 2000 (4).
Given the growing importance of asymmetric synthesis and the techniques needed for accurate determination of optical purity, we felt it necessary to develop an experiment for an advanced undergraduate laboratory to better prepare chemistry majors concentrating in organic synthesis. This experiment describes the resolution of trans-cyclohexane- 1,2diamine using either enantiomer of tartaric acid and the determination of the optical rotation employing polarimetry and the enantiomeric excess (ee) of a derivative by HPLC. The resolution relies on the large difference in solubilities of the diastereomeric tartrate salts formed on addition of racemic diamine to one of the enantiomers of tartaric acid in hot water (eq 1).
On cooling, one of the diastereomeric salts is much less soluble and crystallizes, allowing isolation by filtration. The specific rotation of this salt is determined using polarimetry. The tartrate salt of the diamine is easily derivatized under basic conditions with m-toluoyl chloride, cleanly affording the bisamide, which is pure by ^sup 1^H NMR and HPLC (eq 2). The optical purity of the...