Integrating Enzymes with Chemocatalysts to Create New Reactions Pathways

• Applicant: Dr. Luis Bering
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426555714

Chemistry plays a key role for the development of a sustainable society. There is a tremendous need for the development of ‘greener’ and environmentally benign processes. Interdisciplinary research at the interface of chemistry and biology can address this global challenge by enabling new and sustainable reaction pathways for the synthesis of valuable products, such as pharmaceutical, agrochemicals and other fine chemicals. A high proportion of pharmaceuticals contain amide bonds and the synthesis of amides is one of the most frequently used reactions in medicinal chemistry. Despite the wide spread of amide bond formation, it faces unsolved problems. The synthesis of amides requires the use of stoichiometric quantities of coupling reagents, which are costly, create significant problems in reaction purification, and lead to large quantities of waste. Furthermore, many reagents and solvents for the synthesis of amides are toxic. Given the urgent need for alternative, cleaner, and more efficient catalytic methods to generate amides, an unprecedented approach for amide bond formation has been developed, by combining chemocatalysis with biocatalysis. Biocatalysis is of increasing importance, due to enzymes’ high control of reactivity and environmentally benign reaction conditions, which are enabled by biocatalysis. However, not every chemical transformation can be achieved by using biocatalysts. In contrast, transition-metal catalysed coupling reactions do not exist naturally in biological systems. Therefore, the combination of both catalyst regimes opens the opportunity for completely new chemical transformations, which cannot be achieved by solely using biocatalysis or chemocatalysis alone. Herein, I report the development of an integrated reaction approach combining the enzyme nitrile hydratase (NHase) with transition-metal catalysed Ullmann-type arylation for the synthesis of amides from readily available organic nitriles. The proposed work for integrated chemo- and biocatalysis has been realised as a highly efficient and unprecedented method for the synthesis of amide bond containing molecules under mild and environmentally benign reaction conditions. The biocatalysts can be readily prepared in large quantities. The chemocatalytic step has been extensively optimised to enable the utilisation of an inexpensive and abundant first-row transition-metal catalyst. The broad scope demonstrates the applicability of the integrated reaction. Further, proof of concept for the synthesis of highly valuable chiral amide building blocks has been successfully realised. Thus, the integration of NHase and transition-metal catalysis represents a completely new and powerful approach for the sustainable synthesis of amides, overcoming the present limitation and drawbacks of established methodologies.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Jason Micklefield, Ph.D.