Chirality: Why Is It Important?

A molecule is said to be chiral if it can exist as iso-mers (called enantiomers) that are nonsuperimpos-able mirror images of each other. We often saythese molecules exhibit “handedness,” after ournonsuperimposable mirror image left and righthands. Enantiomers rotate plane-polarized light bythe same angle but in opposite directions; however,the importance of this type of isomerism goes farbeyond this rather curious behavior. In fact, manyof the molecules produced by organisms exhibit aspecific handedness. This is important because theresponse of an organism to a particular moleculeoften depends on how that molecule fits a particu-lar site on a receptor molecule in the organism.Just as a left hand requires a left-handed glove, aleft-handed receptor requires a particular enan-tiomer for a correct fit. Therefore, in designingpharmaceuticals, chemists must be concerned aboutwhich enantiomer is the active one—the one thatfits the intended receptor.

Ideally, the pharmaceutical should consist of thepure active isomer. One way to obtain the com-pound as a pure active isomer is to produce thechemical by using organisms, because the produc-tion of biomolecules in organisms is stereospecific(yields a specific stereoisomer). For example, aminoacids, vitamins, and hormones are naturally pro-duced by yeast in the fermentation of sugar andcan be harvested from the ferment. Biotechnology,in which the gene for a particular molecule is in-serted into the DNA of a bacterium, provides an-other approach. Insulin is now produced in thisway.

In contrast to the synthesis of biomolecules byorganisms where a specific isomer is produced,when chiral molecules are made by “normal”chemical procedures (reactants are mixed and al-lowed to react), a mixture of the enantiomers isobtained. For example, when one chiral center ispresent in a molecule, normal chemical synthesisgives an equal mixture of the two mirror imageisomers—called a racemic mixture. How does onedeal with a pharmaceutical produced as a racemicmixture? One possibility is to administer the drugin its racemic form, assuming that the inactiveform (50% of the mixture) will have no effect,positive or negative. In fact, this procedure is beingfollowed for many drugs now on the market.However, it is a procedure that is growing increas-ingly controversial as evidence mounts that the “in-active” form of the drug may actually producedetrimental effects often totally unrelated to the ef-fect of the active isomer. In effect, a drug adminis-tered as a racemic mixture contains a 50% impu-rity, the effects of which are not well understood.

The alternative to using racemic mixtures is tofind a way to produce the substance as a pure iso-mer or a way to separate the isomers from theracemic mixtures. Both of these options are diffi-cult and thus expensive. However, it is becomingincreasingly clear that many pharmaceuticals mustbe administered as pure isomers to produce the de-sired results with no side effects. Therefore, a greatdeal of effort is now being directed toward the syn-thesis and separation of chiral compounds. ■