Molecular and Engineering Perspectives of the Biocatalysis Interface to Chemical Synthesis

R. Wohlgemuth

Abstract
The sustainable use of limited resources by nature to provide target molecules with biocatalytic reactions continues to be a role model for chemical synthesis. The application of biocatalysts to functional group transformations is shaped by the various parallel influences like e.g. the search for selectivity, the shift from fossil-based to biobased raw materials and the economy of molecular transformations like atom economy and step economy. As safety, health and environment issues are key drivers for process improvements in the chemical industry, the development of reactions or pathways replacing hazardous reagents is another major factor determining the sequence of molecular transformations from raw material to product. Biocatalyst production technologies and integrated process engineering have been instrumental in the establishment of biocatalytic reaction steps in chemical synthesis. The inherent properties of biocatalysts make them the privileged catalysts for highly selective asymmetric molecular transformations like e.g. hydrolysis reactions, oxidation reactions, carbon-carbon bond formation reactions as well as molecular unit transfer reactions. The universe of six enzyme classes provides a tremendous goldmine for discovering improved versions of enzymes with known functions as well as for finding completely novel enzymes. With the growing collection of biocatalytic reactions, the retrosynthetic thinking from chemical synthesis can be applied to biocatalysis as well. Once the feasibility of a biocatalytic reaction has been proven, up- and downscaling experiments have been useful for engineering the most adequate process design. In the case of the first large-scale biocatalytic Baeyer-Villiger oxidation, the debottlenecking of the substrate feed and product recovery, final purification and overcoming thermodynamic limitations have been essential in establishing bioprocesses with high yields of enantiopure products. These downscaling experiments in conjunction with new analytical techniques have proven useful also in the case of asymmetric synthesis of natural compounds. Spatial and temporal organisation of biocatalysts, reactants or products is another interesting engineering option for biocatalytic process design. The interdisciplinary character of the dead ends and locks between chemistry, biology and engineering requires investigations of the interfaces. Communication across scientific and technological disciplines including the value creation perspective is important for the development of a better synthesis for the final product-in-the-bottle. Whether the successful problem solution will come from the engineering of substrates, reaction media, process conditions or from the search for better and new enzymes, progress in the understanding of the molecular mechanisms of enzyme action will be key for the further development of the science of synthesis with its challenges towards the more difficult and more complex target molecules.

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Keywords
Atom economy, step economy, redox economy, enzymatic resolution, asymmetric synthesis, biotransformation, biocatalysts, oxidoreductases, transferases, hydrolases, lyases, biocatalytic process design, downstream processing, scalability