Connecting Carbon: The Friedel-Crafts acylation goes biocatalytic

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Follow up with the second article of “Connection carbon”. Missed to read the first part? Here you go!

Among numerous carbon-carbon coupling reactions in organic synthesis, the Friedel-Crafts acylation enables the direct connection of aromatic compounds with carbonyl moieties. It is therefore one of the most popular chemical transformations and extensively used. The resulting products- aromatic ketones- are valuable building blocks and relevant to a range of industrial sectors, including the pharmaceutical, biotechnological and fine chemical industry. acib pioneers in developing a biocatalytic equivalent for this fundamental reaction, thereby exploiting a so-far little investigated cofactor-independent acyltransferase. But why considering enzymes to do this reaction?

“The traditional, chemical Friedel-Crafts acylation mostly works with stoichiometric amounts of water-sensitive or acidic reagents, at high temperatures, in organic solvent and produces a lot of waste,” explains Nina Schmidt, a researcher at acib. The goal of the project is simple: rendering the Friedel-Crafts reaction more eco-friendly.

In the enzymatic Friedel-Crafts acylation, which runs in aqueous conditions, the carbonyl moiety derived from an acyl-donor compound is directly transferred to the aromatic ring of the desired acyl acceptor substrate. “The transferase irreversibly acylates a broad range of phenol derivatives to the respective aromatic ketones with excellent positional selectivity and isolated yields up to 95%. Another benefit is that this enzyme requires no metal- or other cofactors, which however most other acyltransferases do,” says Nina Schmidt.

The enzyme is highly selective for aromatic carbon atoms (C-acylation) and unlike other acyltransferases does not catalyze the acylation of hydroxy (O-acylation) or amine groups (N-acylation). This is a major advantage, because the phenolic substrates can be acylated without requiring protection of the adjacent hydroxy groups.

Although the donor scope is currently limited to small, two-carbon units, the acyl sources that can be used are environmentally safe. Isopropenyl acetate is a small, commercially available ester, which is commonly employed in lipase reactions. The acyltransferase utilizes the acyl group of the donor isopropenyl acetate, leaving acetone behind as co-product. Acetone is non-toxic and easily separated from the valuable products.

This work is based on: 
NG Schmidt, T Pavkov-Keller, N. Richter, B. Wiltschi, K. Gruber, W. Kroutil: Biocatalytic Friedel-Crafts Acylation and Fries reaction. 2017 Angew Chem Int Ed 56
Picture credits: pixabay