In our series "Insider Views," Next Wave asks leading scientists to give a bird's-eye view on their particular field of research and to explain current trends that may determine not only the future research efforts but also the employment situation of young academics in this field.

Catalytic Cascades: New Concepts in Molecular Syntheses

Chemistry (along with electronics and information technology) may have dominated the scientific scene in the 20th century, but by the turn of the millennium, many chemists thought that organic synthesis was done and dusted. After 150 years of eventful developments, how could the field possibly continue to surprise us? Biology and biotechnology, it was predicted, would be where the exciting science was to be found in this new century. But, this is not the way things work in science. Just as physics did not end with the mastering of electricity but evolved into electronics and ICT, modern molecular biology is teaching chemists so many new lessons that new avenues for molecular syntheses are opening up all around. In chemical synthesis, stoichiometric processes (using mostly equimolar amounts of reagents) might become obsolete, but catalysis is only half way to being fully exploited.

The scheme below gives an interesting insight into the history of and future prospects for synthesis. Whereas the petrochemical industry has already stepped outside the box of traditional stoichiometric synthesis, the fine chemical industry has only made a first step in that direction. Biocatalysis, the use of enzymes in organic synthesis, is helping to reduce waste generation in the industrial-scale production of pharmaceuticals--from 10 to 50 kg per kilogram of end product 25 years ago to 1 to 5 kg today--but pharma and fine chemicals are still a long way from achieving the almost waste-free processes found in the modern petrochemical industry. Still the incentive is there--improved process economics and a reduced environmental impact have arrived hand in hand with the introduction of biocatalysis.

The petrochemical industry has already gone through several generations of catalysis, as exemplified by the production of polyolefins using various forms of Ziegler-Natta catalysis through to catalysis by metallocenes. So far, though, the fine chemical industry has not been successful in translating petrochemical catalysis to the more complex and fragile life science molecules, and is now looking for new catalysis methodologies, additional to biocatalysis.

New developments can be expected along the two axes of the scheme shown. On the vertical axis, we can expect to see more efficient individual catalysts. But real breakthroughs will come from the application of multicatalyst systems. Enzyme tandems in bioredox reactions are already emerging. One enzymatic reaction performs the oxidation while the other regenerates the oxidation agent in a parallel reduction. In addition, the first examples of combinations of enzyme- and metal-based catalysts have reached industry. With such a system, secondary chiral alcohols are resolved by enantioselective acylation using an enzyme, whereas the transition metal sets up an equilibrium between the two enantiomers of the substrate. It is envisaged that a second enzyme could be introduced to the system to remove the acyl function again, resulting in overall transformation of a racemic alcohol to a single optically pure enantiomer in quantitative yield.

Researchers are hoping for fascinating results from selective catalyst positioning. Most reactions are carried out under homogeneous conditions. Heterogeneous conditions are used to enhance catalyst efficiency and selectivity and to ease work-up procedures but are hardly ever employed to allow different reactions to take place at different locations. In nature, however, this is a very common occurrence. Contrary to earlier thinking, the biological cell is a highly organized structure, and enzymes do not simply float around freely. Biosynthetic selectivity is achieved through discriminating transport systems to take the substrate to the reactive site, highly selective conversions at this site, and selective transport systems for the product as well. All these systems are being unraveled more and more and provide inspiration for the development of new catalytic configurations which would allow several conversions via a dedicated sequence of catalytic sites.

The scientific literature outlines a few examples of these cascades, mainly in enzyme systems and which are not of great practical use yet. Our expectations, however, should be high. Modern biotechnology, through the genomics revolution in combination with HTE (high-throughput parallel experimentation) and HTS (high-throughput screening), will allow process development and catalyst screening in a much shorter time, and in much larger numbers, than ever before. This merger of molecular biology, micro systems technology (furnishing the HTS and HTE techniques), and chemical catalysis will revolutionize the way we synthesize molecules. All sectors of the chemical industry will be affected, although not always for the same reasons. In fine chemicals, process efficiency and the shortening of development times are important drivers. In the petrochemical industry, process efficiency is also still a driver, but replacement of fossil resources by more sustainable raw materials derived from biomass is becoming an important second driving force.

Returning to the scheme, we have also taken a few steps along the horizontal axis. This, in fact, is also a move of major importance. So far, chemistry has been dominated by methodology which involves making one conversion at a time, each reaction being followed by a separation, purification, or some other physical operation. Just as doing experiments one by one will be replaced by high- and medium-throughput parallel experimentation (running four, 100, 1000, or even more experiments in one robotized run), so single-step synthesis will become obsolete as well.

Again the biological cell serves as an example. Here a great number of reactions take place at the same time, in both sequential and parallel reactions. Intermediates are transported from one reaction site to the other 'just in time', and because their concentrations are kept low, side reactions are prevented and complicated molecular functionality is possible. In biological terms this is the metabolic pathway. Molecular synthesis can build on these insights in two ways. On one hand, using the cell as example, catalytic cascades will be developed for multistep synthesis in one pot as also described above. On the other hand, biosynthesis (traditionally called fermentation) will take a new shape. The metabolic pathway just described can be genetically engineered to eliminate, modify, or add enzymatic reaction sides. This will allow biosynthesis of nonnatural products. First efforts to produce molecules such as caprolactam (analogous to the amino acid lysine) and hydroxyphenylglycine (structurally similar to tyrosine) are already under way.

The next generations of scientist will have to do most of the work envisaged above. They will fully master the advantages of microsystems technology, both at laboratory scale and at manufacturing level. They will design the catalytic cascades and the (bio-)catalytic devices to run multi-step reactions, either at nano-, micro-, mini-, or conventional macro-scale. Any study based on molecular insight can serve as an entry to this fascinating world of the future: molecular biology, molecular life sciences, chemistry, nanoscience, process engineering or process architecture.

Read more about catalysis research in the Netherlands as well as Dutch and European research initiatives in the second part of this article "Catalysis Research in the Netherlands".

Alle Bruggink is employed by DSM Corporate Technology with responsibility for Technology & Sustainability. He is chair of NWO-ACTS and part-time professor in industrial chemistry at the University of Nijmegen. In the 30 years of his professional career he has worked in the fine chemical and life sciences industries in the areas of research, company strategy, international market development, technology transfer, and university-industry co-operations.