Enantiomers, asymmetric synthesis physical properties

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

There are many synthetic techniques for stereoselective synthesis and because of the importance much research is currently devoted to expanding these techniques. Omeprazole, marketed as Prilosec , was the first proton pump inhibitor and is used as a treatment for gastric ulcers. It is a racemic mixture. The S enantiomer has better pharmacokinetics and pharmacodynamics than the racemic mixture and therefore higher efficacy in controlling acid secretion [38]. The S enantiomer is called esomeprazole and is marketed as Nexium . Nexium has annual sales of 8.4 billion [39]. The chiral center is at the sulfur and the enantiomers can be separated by derivatizing with a R-(-) mandelic acid chiral auxiliary to form two diastereomers. Unlike enantiomers, diastereomers have different physical properties. The diastereomers can be separated by HPLC and then the chiral auxiliary removed to afford each of the omeprazole enantiomers. Alternatively, the sulfide precursor can be asymmetrically oxidized to form esomeprazole in 99.99% enantiomeric excess (ee) [40]. Enantiomeric excess means the excess amount of one enantiomer over the racemic mixture. If something is 80% ee that means that 20% is a racemic mixture and the other 80% is excess of that enantiomer. In this example, for 100 g, there are 90 g of the predominant enantiomer and 10 g of the lesser enantiomer in other words, 20 g is a racemic mix (lOg of each enantiomer) and 80g is excess enantiomer. 

The synthesis of chiral molecules in laboratories results in the formation of a racemic mixture, an equal percentage mixture of both enantiomers. The extraction of enantiomers from racemic mixtures is almost impossible because of the identical physical and chemical properties of the enantiomers. Racemic mixtures are optically inactive, as they contain equal amounts of the D and L isomers. Some big organic molecules may contain more than one asymmetric carbon atom in their structure. An increasing number of asymmetric carbon atoms (n) increases the number of enantiomers by a factor of 2n. 

---