Advancing Biocatalysis One Process at a Time; Autonomous Optimisation of Chemoenzymatic Cascades in Continuous Flow

Professor Francesca Paradisi Advancing Biocatalysis One Process at a Time Matthew Takle Autonomous Optimisation of Chemoenzymatic Cascades in Continuous Flow

Professor Francesca Paradisi Dept. of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern Switzerland

Title: Advancing Biocatalysis One Process at a Time

ABSTRACT 

Advancing Biocatalysis One Process at the Time Professor Francesca Paradisi Dept. of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern Switzerland (S)-Amine, NADP+, glucose EtOAc HEWT KRED BmGDH Ambersep 900 OH H2O PLP, L-alanine, glucose, glucuronic acid, NADP(H) Pyruvate, PLP The move towards sustainable syntheses is a widespread effort which sees academia and industry developing new strategies and solutions. But why is it that biocatalysis, in general, is still not part of the standard toolbox of a chemist? Enzymes are felt to be challenging to work with, they would require a major revolution of the set-up of an existing process, it appears easier to just replace the catalyst with a more efficient newer one which can be just slotted in, in a well-established multi-step chemical cascade. In addition, the requirement for aqueous conditions for the biocatalysts is often limiting in terms of concentrations and scalability. From a process point of view, water is not so green if one needs ten times the volume. And what do we do with the dirty water? Our recent work has focussed on finding ways to make enzymatic steps just another possibility to be at least considered as an option when designing a multi-step synthesis. The ability to immobilize enzymes through versatile chemistries and supports, is a pillar of our group, which has enabled very successful continuous flow processes (Fig. 1). But again, we started thinking at the additional waste we generate when we discard the immobilized biocatalyst. Can we do better? Here I will present our latest efforts in the field. [2-4] QP-BZA EtOAc Ketone, Alcohol PLP, glucose, NADP(H) (S)-Alcohol Figure 1: Flow reaction to convert amines into alcohols through a fully self-sustained closed-loop approach References [1] Benítez-Mateos, A. I.; Roura Padrosa, D.; Paradisi, F. Multistep Enzyme Cascades as a Route towards Green and Sustainable Pharmaceutical Syntheses. Nat. Chem. 2022, 14 (5), 489–499. https://doi.org/10.1038/s41557-022-00931-2. [2] Rassati, B.; Reusser, J.; Robustini, L.; Ben Mariem, O.; Pavlova, A.; Eberini, I.; Paradisi, F. Highly Efficient One-Pot Bi-Enzymatic Cascade to 5-MeO-Tryptamine. ACS Catal. 2025, 15 (24), 21115–21123. https://doi.org/10.1021/acscatal.5c07706. [3] Bojanov, G.; Swit, J.; Paradisi, F. Going Full Circle: Dynamic Covalent Enzyme Immobilisation via Visually Trackable Boronate Esters. Chem. Sci. 2026, 17 (17), 8513–8520. https://doi.org/10.1039/D5SC08585C. [4] Aziziyan, F.; Guerrini, U.; Eberini, I.; Molinari, F.; Paradisi, F. Functional Characterization and Substrate Scope Expansion of Novel Cytochrome P450 Homologues Using a Fdx-FdR Fusion System. Catal. Sci. Technol. 2026, 16, 5250 – 5259 https://doi.org/10.1039/D6CY00532B. [5] Aziziyan, F.; Sgroi, E.; Frati, G.; Mariem, O. Ben; Eberini, I.; Tolomelli, A.; Paradisi, F. Mining for Novel Tryptophanase A: Extremophilic Organisms Ardenticatena Maritima and Haloarcula Japonica as Alternatives to E. Coli in the Synthesis of Tryptophan Analogues. ChemCatChem 2026, 18 (14). https://doi.org/10.1002/cctc.70908. 

BIOGRAPHY 

Prof. Paradisi graduated with a BSc and then a PhD in organic chemistry from the University of Bologna. In 2002 she joined the group of Prof. Engel at University College Dublin for her post doc and started working in the area of Biocatalysis. She got her first academic position in the School of Chemistry in UCD in 2006 where she remained till 2016. She was recruited then by the University of Nottingham as Associate Professor in Biocatalysis and promoted to Full Professor in 2019. In the same year however, she was offered the Chair of Sustainable Pharmaceutical Chemistry at the University of Bern and relocated to Switzerland. Flow-biocatalysis and enzyme immobilization are core technologies of the Paradisi Lab. She is the recipient of the Green and Sustainable Chemistry Award 2021 jointly sponsored by the Swiss Chemical Society and Syngenta for her ground-breaking work in developing eco-friendly and ultra-efficient biotransformations for the synthesis of high-value chemicals, dramatically increasing the applicability of biocatalysis. She is the co-founder of the start-up inSEIT (2022). In 2024 she was also acknowledged by the ACS as a “Sustainability Star” for her effort in developing a sustainable future.

Dr Matthew Takle Research Fellow, Clayton group, School of Chemistry, Leeds

Title: Autonomous Optimisation of Chemoenzymatic Cascades in Continuous Flow

ABSTRACT Autonomous Optimisation of Chemoenzymatic Cascades in Continuous Flow Dr Matthew Takle Research Fellow, Clayton group, School of Chemistry,Leeds Autonomous optimisation of reactions is a powerful tool for streamlining the development of chemical processes.[1-2] The use of Bayesian optimisation algorithms in combination with automated flow reactors (Figure 1) serves to reduce the number of experiments required to reach optimal reaction conditions, reduces the amount of material consumed during the optimisation, and allows for the redistributions of resources to other areas of research that cannot yet be automated. Previously, the application of Bayesian optimisation in flow had been limited to chemical transformations, however recently we have demonstrated the ability to apply this methodology to biocatalytic transformations.[3] Combining the ability to autonomously optimise both chemical and biocatalytic reactions has opened the door for the streamlined development to autonomously optimised telescoped chemoenzymatic cascades in flow. These cascades serve as a powerful synthetic methodology which creates highly selective, sustainable and scalable routes to bioactive molecules. In this work we combine the use of high-throughput screening, rational selection, and autonomous optimisation in flow to deliver a chemoenzymatic cascade synthesis of a key intermediate of AstraZeneca’s recently FDA approved treatment for Hypotension, Baxdrostat. Figure 1. Automated Bayesian Optimisation Flow Reactor System. References [1] Clayton et al, React. Chem. Eng., 2024, 9, 308 [2] Kappe et al, ACS Sustainable Chem. Eng. 2024, 12, 10002−10010 [3] Clayton et al, Chem. Sci., 2025, 16, 18783–18790

BIOGRAPHY 

Matt completed his PhD at Imperial College London under the supervision of Professor Mimi Hii, in collaboration with BASF. His research focused on developing a chemoenzymatic dynamic kinetic resolution methodology for the synthesis of chiral amines in flow. He subsequently joined the Innovative Continuous Manufacturing of Industrial Chemicals Partnership between Imperial and BASF as a postdoctoral researcher, where he scaled up his PhD research from 1 g to 100 g. Matt then moved to the University of Leeds, where he joined Adam Clayton’s group as a postdoctoral researcher, focusing on the autonomous optimisation of chemoenzymatic cascades in flow.