The key point about resolution is that we must bring together two stereogenic centres in such a way that there is a degree of interaction between them: separable diastereoisomers are created from inseparable enantiomers. In the last two examples, the stereogenic centres were brought together in covalent compounds, esters. Ionic compounds will do just as well—in fact, they are often better because it is easier to recover the compound after the resolution.

An important example is the resolution of the enantiomers of naproxen. Naproxen is a member of a family of compounds known as non-steroidal anti-inflammatory drugs (NSAIDs) which are 2-aryl propionic acids. This class also includes ibuprofen, the painkiller developed by Boots and marketed as Nurofen.

Both naproxen and ibuprofen are chiral but, while both enantiomers of ibuprofen are effec tive painkillers, and the drug is sold as a racemic mixture (and anyway racemizes in the body) only the (S) enantiomer of naproxen has anti-inflammatory activity. When the American pharmaceutical company Syntex fi rst marketed the drug they needed a way of resolving the racemic naproxen they synthesized in the laboratory. Since naproxen is a carboxylic acid, they chose to make the carboxylate salt of an enantiomerically pure amine, and found that the most effective was a glucose derivative. Crystals were formed, which consisted of the salt of the amine and (S)-naproxen, the salt of the amine with (R)-naproxen (the diastereoisomer of the crystalline salt) being more soluble and so remaining in solution. These crystals were filtered off and treated with base, releasing the amine (which can later be recovered and reused) and allowing the (S)-naproxen to crystallize as its sodium salt. This is an unusual resolving agent as a simpler amine might usually be preferred. However, it makes the point that many resolving agents may have to be tried before one is found that works.

Chiral drugs You may consider it strange that it was necessary to market naproxen as a single enantiomer, in view of what we have said about enantiomers having identical properties. The two enantiomers of naproxen do indeed have identical properties in the laboratory, but once they are inside a living system they, and any other chiral molecules, are differentiated by interactions with the enantiomerically pure molecules they fi nd there. An analogy is that of a pair of gloves—the gloves weigh the same, are made of the same material, and have the same colour—in these respects they are identical. But interact them with a chiral environment, such as a hand, and they become differentiable because only one fits.

The way in which drugs interact with receptors mirrors this hand-and-glove analogy quite closely. Drug receptors, into which drug molecules fit like hands in gloves, are nearly always protein molecules, which are enantiomerically pure because they are made up of just L-amino acids. One enantiomer of a drug is likely to interact much better than the other, or perhaps in a different way altogether, so the two enantiomers of chiral drugs often have quite different pharmacological effects. In the case of naproxen, the (S)-enantiomer is 28 times as effective as the (R). Ibuprofen, on the other hand, is still marketed as a racemate because the compound racemizes in the bloodstream.

Sometimes, the enantiomers of a drug may have completely different therapeutic properties. One example is Darvon, which is a painkiller. Its enantiomer, known as Novrad, is an anticough agent. Notice how the enantiomeric relationship between these two drugs extends beyond their chemical structures! In Chapter 41 we will talk about other cases where two enantiomers have quite different biological effects.

مواضيع ذات صلة

Significance of the SN2 rate equation

Mechanisms for nucleophilic substitution

Separating enantiomers is called resolution

Chiral compounds with no stereogenic centres

Diastereoisomers can arise when structures have more than one stereogenic centre

Absolute and relative stereochemistry

Diastereoisomers can be chiral or achiral

Dia stereoisomers are stereoisomers that are not enantiomers

The rotation of plane-polarized light is known as optical activity

R and S can be used to describe the configuration of a chiral centre

Many chiral molecules are present in nature as single enantiomers

Stereogenic centres