Developing chiral surfaces for enantioselective chemical processing

Abstract

A ny object that cannot be superimposed upon its mirror image is said to be chiral, and the two mirror image forms are called enantiomers. A person’s left and right hands are one familiar macroscopic example of chiral objects. Chirality is of immense interest in chemistry, because many organic molecules are chiral. Any atom in a molecule that is tetrahedrally bonded to four different functional groups makes that molecule chiral. Alanine is a simple example of a chiral molecule, having a central C atom that is bonded to H, CH3, NH2, and COOH. More complex chiral molecules can have many chiral centers. From a bulk physicochemical perspective, the chirality of organic molecules is rather uninteresting; the solubility, density, melting point, etc., of the two enantiomers of a chiral molecule are identical. This simple fact makes it impossible to separate enantiomers using the typical tools of chemical engineering. A related reality is that the typical methods of chemical synthesis do not distinguish between enantiomers of a chiral product, so a typical chemical synthesis generates a racemic mixture, that is, an equimolar mixture of the molecule’s enantiomers. The importance of molecular chirality lies in the biological effects of chiral chemicals. A fundamental property of all known living organisms is that they are homochiral. That is, life uses only a single enantiomer of each chiral molecule. As a result, the bioactivity of chiral chemicals is often highly dependent on which enantiomer of the chemical is ingested by the organism. A simple example is limonene, a chemical with two enantiomers which have quite different odors. A more striking example is the illicit drug cocaine. One enantiomer of cocaine has well documented biological effects, although the other enantiomer has no comparable effects. The differing bioactivity of the enantiomers of chiral compounds is of great importance in the pharmaceutical industry. If the enantiomers of a pharmaceutical compound have different bioactivities, then a racemic mixture of the enantiomers will, at best, have lower efficacy than the enantiomerically pure form. In other cases, the undesirable enantiomer can cause unpleasant or dangerous side effects. To give just one example, levalbuterol, the enantiomerically pure form of an asthma medication, causes significantly fewer side effects than the racemic form, which is marketed in the U.S. as albuterol. Creation and purification of enantiomerically pure compounds has many ramifications in the pharmaceutical industry. Worldwide sales of enantiopure drugs exceeded $U.S.225 billion per year in 2006, with an annual growth rate of 10%. If a compound is currently marketed in its racemic form, the corresponding enantiopure compound can be covered by a new patent, thus, extending its protected lifetime. Moreover, the U.S. FDA mandates that each enantiomer of a new compound be tested separately prior to FDA approval, even if the compound that will be marketed will be a racemic mixture This situation means that all pharmaceuticals must be produced in enantiopure form in at least limited quantities. Because of the importance of producing enantiopure chemicals, numerous methods exist for enantioselective chemical processing. A concise description of these methods has been given in this journal by Rekoske. Broadly speaking, these methods can be divided into efforts to synthesize chemicals in an enantiopure form rather than a racemic mixture and methods for separating enantiomers from racemic (or other) mixtures. We will refer to both of these approaches as enantiospecific processing. The former approach is known as asymmetric synthesis, and it defines an important field within organic chemistry. Asymmetric synthesis is dominated by the use of homogeneous catalysts that are themselves chiral. Although asymmetric synthesis is practiced widely, the use of homogeneous catalysts can Correspondence concerning this article should be addressed to D. S. Sholl at david.sholl@chbe.gatech.edu, and A. J. Gellman at gellman@cmu.edu