A DYNAMIC AND FLEXIBLE MANUFACTURING PLATFORM: INTENSIFYING BIOCATALYSIS FOR FRAGRANCE AND API PRODUCTION

Chemists can make novel compounds and materials, but the tools of synthetic methodology must be continuously expanded and improved for the sustainable production of compounds and materials as the needs from society for new or improved medicines and other compounds are high. Environmentally benign processes to satisfy that demand will increase the quality of life in many aspects. In our proposed research program, we will introduce a new method for mixing solutions during a reaction. The benefits of such high-performance mixing are numerous, shortened reaction times and therefore much higher productivities are envisioned which we could already demonstrate during preliminary experiments. In close collaboration with an SME company, Bioextractions Wales, we plan to synthesise fragrance molecules using this approach. After having established the principle and taken first steps to upscale some of the processes with the help of larger equipment available at BioExtractions Wales, we will extend the use of biocatalytic processes to the production of compounds (API's) necessary for the synthesis of drug molecules. Also, these technically more demanding reactions will be performed on a large scale at the companies' site. In addition, we will investigate the 'strength' of mixing and the relation to the outcome of the enzymatic reactions, before introducing further and automated optimisation through inline analysis of the reaction mixtures. This will all support the overall target of this proposal, which is the development of new and efficient processes for the environmentally friendly and resource-cautious industrial-scale synthesis of compounds used as fragrances and for the synthesis of drugs.

We will develop biphasic biocatalytic reactions using high-performance counter current chromatography (HPCCC) equipment for the investigation and use of intensified mixing profiles. This new methodology will be applied for the synthesis of flagrance molecules and of API's as examples of high-value molecules using esterases and transaminases. Combination with automated online analysis will lead to drastically shortened optimisation times and to the development of new and improved reaction protocols. Scale-out of the developed processes will provide larger quantities of flagrance and API molecules.

We propose a highly focused programme of research with the specific objective of using high performance liquid / liquid extraction devices which leads to intense mixing for reactions towards the biochemical synthesis of fragrance and API molecules.
Successful equipment evaluation and the development of promising biotransformations under intense mixing conditions will be demonstrated by target syntheses of fragrance and API compounds. The versatility of the methodology for commercial exploitation involves the development of a larger scale synthesis using scale-up equipment. Such large volume high performance liquid / liquid extraction devices are available at BioExtractions Wales (BEW) where a growth of productivity up to pilot-scale will performed. Our link with BEW will be strongly enforced in the research program proposed here. In addition, the Wales Spin-Out Program from the Welsh Assembly also provides start-up funds and guidance for SME's.

Communications, engagement & outreach - Knowledge
Results from the proposed research will be disseminated through publications in highly rated peer reviewed journals that have a firm commitment to Open Access. Prof. T. Wirth is heavily involved in Open Access publishing. He is Chairman of the editorial Board of ChemistryOpen (Wiley-VCH) and an editorial board member of ScienceOpen. Further dissemination of results will be made by publication of review articles and presentations at national and international conferences. Several opportunities have been identified for participating in outreach activities along with the local RSC Education Coordinator for Wales. These include involvement at science festivals such as the Urdd Festival, National Eisteddfod of Wales, Cardiff Science Week and Chemistry Week. We will organize an International Workshop on Industrial Biotransformations in Cardiff in 2021/22 with a focus on flow biochemistry, which will be done together with other recently appointed lecturers in biological chemistry in Cardiff, Dr. Yi Jin and Dr. Louis Luk. With sponsors from industry and with support of the local section of the RSC (Royal Society of Chemistry) and the School of Chemistry at Cardiff University, we aim to invite a series of established lecturers from industry and academia from different countries.

Capacity and involvement - People
Impact on people will be achieved through outreach activities which are dissemination initiatives directed at the general public. The primary goal is to create awareness of the importance of our research to society and to raise awareness of the environmentally friendly processes we are developing in this research. The public's perception of chemistry is still frequently colloquially misrepresented, and one aim of this work is to change the negative connotations associated with chemistry in the public's eye. As enzymes are biocatalysts which everyone can easy associate with, the connection to intensifying such biochemistries can be made easily and, through this route, get an access to the people's perception.
Biosynthetic transformations are extremely valuable tools for chemists. The proposed research will have a profound impact on the scientific community and, particularly, give a new dimension and outlook for intensifying reactions in biphasic systems. It will pave a new era for exploitation of environmentally benign chemistry towards the synthesis of important target molecules. This will be demonstrated in this proposed research with the synthesis of fragrance molecules and of advanced pharmaceutical intermediates - both compound classes the general public can easily relate their experience to. Enzyme-catalysed reactions are a typical green way of synthesis in comparison to conventional chemistry. The proposed work will create an innovative path towards synthesis, which will broaden the prospect for many biotransformations.