Redox Neutral Biocatalysis: Intramolecular Bio-Tishchenko Reaction

A common goal of chemists active in the broad field of organic synthesis is to design novel synthetic routes that are not only superior in terms of yield and selectivity and are cost-effective, but also display a low environmental impact. Here, we propose an unconventional approach to invent and design biological counterparts with reduced ecological footprint by learning from existing chemical systems. The aim is to render chemical processes more elegant and attractive to approach the Holy Grail in chemistry of `1+1=1`, by inventing new systems derived from nature. The project `Redox Neutral Biocatalysis: Intramolecular Bio-Tishchenko Reaction and Beyond` will explore the catalytic activity of proteins in the intramolecular Tishchenko reaction. In this chemical reaction, two similar parts of a molecule undergo a single transformation in opposite direction: one part gives electrons away, which are captured by the second part. Through this process, the two parts are merged and generate one single product with new functionality. Biocatalysis is an enabling technology that intrinsically contributes to the development of sustainable processes by allowing the following: use of less or no toxic reagents and catalysts, operating under mild conditions and high selectivity. All these advantages result from the use of proteins as natural catalysts (also denoted as enzymes). So far, no enzyme has been shown active in the Tishchenko reaction, and we propose to investigate the possibility to design the first example of this reaction by exclusively using biological tools. This highly atom-efficient biotransformation involves neither reagent nor by-product, and is thus eminently attractive from a sustainability standpoint. The project will investigate a broad variety of starting materials and identify ideal conditions for the generation of single products in high selectivity. In our preliminary study, we showed that a model substrate can be transformed as desired, and the methodology developed will be further applied. It consists in the use of purified proteins for the transformation of pre-defined molecules and the study of their influence on product formation. Overall, the reaction does not need other reagents, does not produce any waste and requires only the action of a single catalyst derived from natural sources. Such simplified biological systems with demonstrated synthetic efficiency are rare. We will here contribute an important milestone toward a more sustainable way of generating chemicals and thereby demonstrate that `1+1=1`.

Biocatalysis is an enabling technology that intrinsically contributes to the development of sustainable processes. Under such considerations, chemical transformations can be performed using less or no toxic reagents, under mild conditions and with high selectivity. All these advantages result from the use of proteins as natural catalysts (also denoted as enzymes). These biological molecules accelerate the speed of a given chemical reaction and thus ensure short reaction times. The project 'Redox Neutral Biocatalysis: Intramolecular Bio-Tishchenko Reaction and Beyond' explored the catalytic activity of proteins in the intramolecular Tishchenko reaction. In this chemical reaction, two reactive parts of a molecule undergo one transformation each in opposite direction: one part gives electrons away, which are captured by the second part. Through this shuffling of electrons, the two parts are merged and generate one product with new functionality. A highly atom-efficient biotransformation taking place mostly in water using alcohol dehydrogenases as enzymes was thereby developed: the number of atoms in the product obtained was comparable to the number of atoms in the starting material at the beginning of the reaction, and neither reagent nor by-product were involved in the synthesis of the targeted products. Such protocol is eminently attractive from a sustainability standpoint, since a new functionality and possibly novel properties can be obtained through internal shuffling of electrons without producing waste. By studying the type of molecules undergoing this particular transformation, it was possible to identify a suitable decoration pattern that was compatible with the alcohol dehydrogenases, ensuring most efficient chemical transformation. The products obtained belong to the class of lactone molecules. Lactones find broad application as ingredients in flavors and fragrances, but also as starting materials for polymers. In this project, one of the lactone products generated could be successfully transformed in polymer while others may be employed as small building blocks in the synthesis of active pharmaceutical ingredients. Finally, we could design a very simple and elegant method to produce new molecules in an efficient and clean process: one substrate was converted into one product in water by a single catalyst derived from natural sources without need for reagents. This is an important milestone toward a more sustainable way of generating chemicals.