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Multidisciplinary Catalysis

Semper Ardens forskningsprojekt | 10/06/2016

Catalysis is one of the most important processes for the formation of molecules. Molecules shaped by catalysis are applied to generate food for more than 7 billion people. Approximately 70 percent of all products are formed by catalytic processes, life as we know it is based on catalysis and 20-25 percent of the world economy is generated by catalysis.

Catalysis can be performed using different concepts, depending on the complexity of the molecules to be formed. Living organisms require catalytic systems which can generate chiral molecules - molecules with non-equivalent mirror-images. Enzyme-, metal-, and organocatalysis are the prime concepts for the formation of chiral molecules.

Organocatalysis allows for the formation of chiral molecules using small organic molecules as catalysts. The field has expanded from being applied to generate chiral molecules for the synthesis of complex molecular structures in academia and on multi-ton scale in industry. Organocatalysis has the advantage that the reactions proceed under environmentally friendly conditions reducing waste and avoiding hazardous chemicals.

• Catalysis is one of the most important processes for the formation of molecules
• Ca 70 percent of products are based on catalysis
• Ca 70 percent of the nitrogen in our body originates from one industrial catalytic process
• 20-25 percent of the world economy depends directly or indirectly on catalysis
• Asymmetric catalysis is the key concept for the formation of chiral molecules having a specific 3-dimensional structure
• Enzyme-, metal- and organocatalysis are the cornerstones of generating chiral molecules

This article will introduce the importance of asymmetric organocatalysis and the potential to expand this field further by innovative multidisciplinary ventures. These involve novel combinations of organocatalysis with photo- and laser spectroscopy, computational chemistry and high-pressure reactions. The purpose of this project is to challenge the formation of novel chiral molecules, which might have the potential to be applied in life-science.

Asymmetric Catalysis

When the spermatozoon enters the egg in the uterus, life is generated. Life as we know it is based on a large number of catalytic reactions and these are the origin of asymmetry in our body and culture.[1] The importance of catalysis for our life and society cannot be over-estimated: 70 percent of all products (volume) originate from catalysis; 20-25 percent of the world economy depends directly or indirectly on catalysis and 70 percent of the nitrogen in our body originates from one industrial catalytic process – the Haber-Bosch process.

Catalysis spans over the entire spectrum of chemistry, biochemistry, molecular biology, materials science, and industry; from simple molecules produced in millions of tons to complex molecular structures made in only a few milligrams. Chiral molecules are the basic molecules for all living and a multidisciplinary cornerstone in many different fields of science.

Enzymes were the starting point for synthetic asymmetric catalysis and have played an important role for more than 100 years. In the last decades of the last century metal catalysis was in focus and since the beginning of the millennium organocatalysis has undergone extensive development.[2] Organocatalysis is now considered to be of equal importance to enzyme and metal catalysis.

Organocatalysis

• Small organic molecules are used as catalysts in organocatalysis
• Organocatalysis allows processes where several chemical bonds are formed in a highly efficient manner
• Organocatalysis is considered to be green chemistry as it reduces hazardous chemicals, solvent waste and the number of manual manipulations.
• Reactions based on organocatalysis can easily be scaled-up from milligram to ton scale.
• Organocatalysis opens up for multidisciplinary catalysis – combination of organocatalysis with photochemistry, femto-second laser spectroscopy, physical- and computational chemistry, and high-pressure reactions

Organocatalysis allows in a simple and sustainable manner to generate complex molecular scaffolds and has over the last 15 years been a highly competitive field. The field has expanded from being applied in enantioselective reactions, which were also possible using enzymes and metal complexes, to novel enantioselective reactions, concepts and activation modes. The advent of organocatalysis has led to new opportunities in the synthesis of chiral molecules, and its application has found its way from academia to industry.

The activation of organic molecules by organocatalysts can be mediated through covalent or non-covalent interactions. Among the organocatalysts used for covalent activation, chiral secondary amines play a central role. Within this category, the diarylprolinol-silyl ethers[3] are among the most extensively applied and have demonstrated excellent stereo-controlling properties for α- and β-functionalisations of aldehydes and α, β-unsaturated aldehydes, respectively. The application of the diarylprolinol-silyl ethers in asymmetric catalysis has provided a number of novel reaction and concept developments for the formation of small chiral molecular building blocks as outlined in Figure 1. The diarylprolinol-silyl ether catalysts used for these different reactions have been commercialised by various companies (Figure 1, right).

Figure 1. Basic activation and reaction concepts for the organocatalytic reactions of aldehydes and unsaturated aldehydes and the commercially available catalysts.

The application of organocatalysis for the formation of chiral molecules has several advantages  e.g. the industry. For instance, organocatalysis is often applied in one-pot reactions where several bonds are formed in a highly efficient manner, while solvent waste and the number of manual manipulations are reduced significantly. Often a single organocatalyst can facilitate multiple steps by virtue of the many activation modes developed. These features combined with the mild reaction conditions often make organocatalysis a green choice compared with other catalytic concepts.[4] Furthermore, the reactions can easily be scaled-up from milligram to ton scale.

The application of these attractive properties of organocatalysis has expanded beyond chemistry in academic ventures to industry. This is exemplified by the synthesis of Telcagepant for the treatment of migraine by the pharmaceutical company Merck.[5] Another pharmaceutical company Novartis has in a patent from 2008 disclosed a process for the formation of Aliskiren for the treatment of hypertension.[6] Furthermore, the organocatalytic concepts in Figure 1 have been applied by fine-chemical companies for the preparation of small chiral molecular scaffolds to be incorporated in more complex molecules.

A critical part of the synthesis of the anti-migraine compound Telcagepant (Figure 2), involves the application of the catalyst shown in Figure 1 developed at Aarhus University. In a one-pot reaction the organocatalyst controls the stereo-chemistry, which defines the final three-dimensional structure of Telcagepant.

Figure 2. Industrial process based on asymmetric organocatalysis for the formation of the anti-migraine compound Telcagepant. The organocatalysts are highlighted in green and to the right the industrial set-up for performing organocatalysis is displayed.

Organocatalysis in Multidisciplinary Catalysis

Organocatalysis has shown the potential to be integrated with other reaction concepts and have recently been combined with transition-metal catalysis and biocatalysis. In the present project we want to develop catalysis in a novel direction by combining organocatalysis in an innovative multidisciplinary manner with photochemistry, femto-second laser spectroscopy, physical- and computational chemistry, and high-pressure reactions. The underlying multidisciplinary concepts will be extended and applied for the development of new classes of reactions for the construction of macrocyclic compounds with the intention to provide both academia and industry with novel concepts to make “smarter compounds” for the future. It can also be formulated in another way: We will create the chiral LEGO-blocks for the future!

References

  1. C. McManus, Right Hand, Left Hand, The Origin of Asymmetry in Brains, Bodies, Atoms and Culture, Harvard University Press, Harvard 1992.
  2. See e.g.: a) Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications (Ed. P. I. Dalko), Wiley-VCH, Germany, 2013; b) Asymmetric Organocatalysis (Ed. B. List), Springer, Germany, 2009.
  3. For recent reviews by the author presenting the potential of the diarylprolinol-silyl ethers in catalysis: a) S. Bertelsen, K. A. Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178; b) K. L. Jensen, G. Dickmeiss, H. Jiang, L. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248; c) B. S. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov, K. A. Jørgensen, Angew. Chem. Int. Ed. 2015, 54, 13860; K. S. Halsskov, B. S. Donslund, B. M. Paz, K. A. Jørgensen, Acc. Chem. Res. 2016, 49, DOI: 10.1021/acs.accounts.6b00008.
  4. L. Albrecht, H. Jiang, K. A: Jørgensen, Angew. Chem. Int. Ed. 2011, 50, 8492
  5. F. Xu, M. Zacuto, N. Yoshikawa, R. Desmond, S. Hoerrner, T. Itoh, M. Journet, G. R. Humphrey, C. Cowden, N. Strotman, P. Devine, J. Org. Chem. 2010, 75, 7829.
  6. G. Sedelmeier (Novartis AG), WO-A1 119804, 2008.