Chemoenzymatic tandem processes for the production of fine chemicals

CERUTTI SERRA LORENZO; LOPEZ-VIDAL MARTIN; ROSSI NICOLAS; POLITANO FABRIZIO; OKSDATH-MANSILLA GABRIELA; BISOGNO ROMAN FABRICIO

Rosario

Workshop; 2023 V encuentro & II Workshop de la Red Argentina de Tecnología Enzimática (Red TEz); 2023

Chemoenzymatic tandem processes for the production of fine chemicalsCerutti-Serra, L. (1); López-Vidal, M. (1); Politano, F (1); Rossi, N. (1); Oksdath-Mansilla, G. (1); Bisogno, F. R. (1). (1) Departamento de Química Orgánica, Facultad de Ciencias Químicas, Instituto en Investigaciones Físico-Químicas de Córdoba, INFICQ, Universidad Nacional de Córdoba, Argentina.lorenzo.cerutti.serra@unc.edu.arWhite Biotechnology have attracted great deal of attention from specialized industries like Pharma, Food, Flavor and Fragance Industries, among other. In this line, setting up tandem processes involving robust and highly selective biocatalytic steps in combination with non-enzymatic reactions it’s a promising alternative to achieve shorter processing times and avoidance of solvent and energy consuming steps related to downstream tasks. For this reason, we proposed a chemoenzymatic approach to prepare both chiral and achiral small molecules, that can be applied as key chemical precursors for industrial processes, taking advantage of the inherent properties of each step involved. Biotransformation had been conducted in small batches, using commercially available enzymes, immobilized ones or lyophilized preparations of E. coli overexpressing the desired enzyme. When possible, reactions were carried out in one-pot, avoiding the isolation of intermediates. These protocols were performed at preparative scale after optimization of experimental parameters such as pH, temperature, co-solvent, enzyme, substrate and cofactor concentration. On one hand, we explore artificial bienzymatic cascades employing hydrolases, redox enzymes, and transferases, such as alcohol dehydrogenases (ADHs) and ω-transaminases (TAs). We were able to successfully obtain enantioenriched amines and alcohols, starting from achiral and easy-to-prepare enol esters. Compounds with one and two chiral centers were obtained with excellent yields and selectivities (up to %99 ee and de) in one-pot, one-step fashion.On the other hand, we combined biocatalysts with photoredox catalysis. This allow us to produce valuable enantioenriched halohydrins starting from racemic or achiral dihaloketones. By means of an asymmetric carbonyl reduction, achieved by ADHs, followed by a selective photocatalytic mono-debromination reduction promoted by blue light exited flavins as photocatalyst.Additionally, we explored an alternative approach that combined light-promoted reaction with biocatalysis. Using commercially available aromatic aldehydes as starting materials, we established a pinacol coupling reaction promoted by violet LED. Subsequently, a combination of biocatalysis and organocatalysis (laccase-mediator system) was employed to oxidize the resulting diols into hydroxyketones and diketones. This two-step process effectively converted a readily available and inexpensive substrate into complex and valuable compounds with very good yields.Moreover, the combination of a biocatalytic preparation of chiral ß-hydroxy selenocyanates, followed by chemical reduction into diselenides, and then a light-promoted oxidation, gave rise to selenium-containing indoles. This process was initially carried out in batch, and then transferred to a continuous flow system, reducing the reaction time from 24 h to 2 h while maintaining good yields. In conclusion, all enzymatic preparations tested proved to be good candidates in multicatalytic systems. The combination of enzymes with different chemical methods enables the preparation of important chiral alcohols and amines in an enantioenriched fashion. Finally, a continuous flow approach is a promising option for process intensification of multicatalytic system involving biocatalysis.