Building a Better Mousetrap … At the Molecular Level

How Sharpless’ chiral catalysts for oxidations are opening up new frontiers

Industrial productivity: it’s one of those terms that most of us hear and don’t think much more about. But it’s at the heart of what makes it possible for manufacturers of everything from prescription drugs to insecticides to create their products at a cost that makes them affordable to the people who need them.

Improved industrial productivity is just one of the results of the work of K. Barry Sharpless. The W.M. Keck Professor of Chemistry at the Scripps Research Institute in La Jolla, CA, Sharpless received the Nobel Prize in Chemistry in 2001 for his pioneering work in developing chiral catalysts for oxidation, along with co-Laureates William S. Knowles and Ryoji Noyori. Together, they opened up a completely new field of research, making it possible to synthesize molecules and material with new properties.

The results of Sharpless’ basic research, supported by a grant from the ACS Petroleum Research Fund, are being used in a number of industrial syntheses, including pharmaceutical products such as antibiotics, anti-inflammatory drugs and heart medicines.

Creating the right kind of molecules

Sharpless focused his research on chiral molecules — molecules that are unique in that they exist in two structural forms (also known as enantiomers) that are mirror images of each other.

Chiral molecules occur naturally, such as in the case of the common amino acid alanine, which can occur as (S)-alanine and (R)-alanine. In the same way, the other cellular components made from these molecules, such as receptors and enzymes, are also chiral and tend to interact selectively with only one or two enantiomers of a given substance.

But there can also be a downside to chiral molecules in industrial applications. To understand why, consider that when one synthesizes alanine in the laboratory, for example, the result is a 50/50 mixture of (S) and (R) enantiomers — a symmetrical result, as it were.

Likewise, in many pharmaceutical products, conventional synthesis in the laboratory results in symmetrical mixtures; and typically, one-half of the molecules created have the desired effect, while the other half are inactive or may even have harmful side-effects. In fact, this phenomenon occurred most infamously in the 1960s, with the development of the drug thalidomide. The problem led scientists to pursue chiral catalysts, which drive chemical reactions toward just one of two possible outcomes — in other words, an asymmetrical mixture.

Better oxidations, better pharmaceuticals

Through his research, Sharpless developed chiral catalysts for oxidations, a broad family of chemical reactions. Atoms, ions, or molecules that undergo oxidation in reactions lose electrons and, in the process increase their capacity to form chemical bonds. In 1980, while working at MIT, Sharpless carried out key experiments that led to a practical method based on catalytic asymmetrical oxidation for producing epoxide compounds, used in the synthesis of heart medicines such as beta blockers and other products.

This method has enabled a far greater amount of structural diversity, and has had very wide applications in both academic and industrial research. A more immediate benefit is that manufacturers of various types of drugs can make their production processes far more efficient — better for the companies, and just as importantly, making them more affordable for the consumers who need them.

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