Biocatalytic Friedel-Crafts-type Acylation

Friedel-Crafts acylation is still one of the most investigated reactions in synthetic organic chemistry. Its versatility in scope and applicability continues to justify its crucial role in the synthesis of complex molecules. Nevertheless, the reaction may ecologically be improved to reduce significantly amounts of hazardous reagents (e.g., acyl chlorides, anhydrides). Moreover, regioselective acylation is very difficult to achieve. Biocatalysis may offer a very promising alternative, if a suitable enzyme is identified. This is because, firstly, enzymes are very selective catalysts. Secondly, biocatalytic reactions can be run in water/buffer avoiding organic solvents. Thirdly, they are environmentally degradable (Green) because they are made from amino acids. Fourth, the reaction conditions are mild (thus 20-40C), which minimizes side product formation. Up to now, to the best of our knowledge, a biocatalytic Friedel-Crafts reaction applied in organic synthesis has not been described yet. Our model studies indicate that one class of enzymes (acetyltransferases) are able to catalyze that reaction (Scheme 1). Application of these enzymes may provide an alternative to chemical Friedel-Crafts acylations. During the project, we will develop that methodology by using a wide range of aromatic compounds, which may be transformed into valuable building blocks for organic synthesis and medicinal chemistry. In the next stage, we will couple acetyltransferases with other enzymes in a cascade, which may provide an easy access to optically pure alcohols and amines. Furthermore, protein engineering will allow to extend the substrate scope of the catalyst to accept a broader spectrum of non-natural compounds. Scheme 1. Biocatalytic Friedel-Crafts-type reaction.

Friedel-Crafts acylation is still one of the most investigated reactions in synthetic organic chemistry. Its versatility in scope and applicability continues to justify its crucial role in the synthesis of complex molecules. Nevertheless, the chemical reaction is based on the harsh reaction conditions (e.g., high temperatures, organic solvents) and hazardous reagents (e.g., acyl chlorides, anhydrides), what is frequently discouraged for industrial scale application due to the large amount of hazardous waste produced. During the project, a biocatalytic alternative to chemical process was developed. First of all, a suitable enzyme (acyltransferase) was identified to transform a wide range of aromatic compounds. Firstly, enzymes are highly selective catalysts, which minimize the formation of side products. Secondly, they are environmentally degradable ("Green") because they are made from amino acids. Thirdly, the established methodology was run in water/buffer system avoiding organic solvents. Fourthly, reaction conditions are mild (thus 20-35C), which reduces the need of energy. These features make enzyme catalysis a versatile and easy-to-use platform for the production of valuable building blocks for organic synthesis and medicinal chemistry. To further extend the substrate scope, a protein engineering approach was performed. Structure-based molecular modelling led to the identification of several amino acids in the enzyme structure, which replacement allowed to accept previously inaccessible non-natural compounds. The properties of acyltransferase variants could be very interesting from an industrial point of view.