Enzymatic Friedel-Crafts Alkylation Using Squalene-Hopene Cyclases

June 14, 2021 / Sabrina Henche, Bettina M. Nestl and Bernhard Hauer

Efficiency and selectivity in forming carbon-carbon bonds determine chemical manufacturing and are crucial for a sustainable society. The Friedel-Crafts (FC) alkylation represents one of the oldest carbon-carbon bond formation reactions and enables the pairing of aromatics and aliphatics. Despite its age and comprehension, FC reactions often suffer from poor selectivity, follow-up reactions, and ultimately low atom economy. Using the Brønsted acid squalene-hopene cyclase from Alicyclobacillus acidocaldarius we have set the stage for highly atom economical and regio- and product selective FC alkylations. Owing to its relaxed substrate specificity, we demonstrated the intramolecular FC alkylation of an unbiased geranyl phenyl ether. Furthermore, screening a mutant library and compared orthologs to gain complete control over product selectivity and increased activity. Molecular docking studies have been performed to gain more insights into these findings. Thus, the applicability of this enzymatic Brønsted acid will facilitate converting more diverse substrates and implementing intermolecular reactions in the future.


ChemCatChem, DOI: 10.1002/cctc.202100452

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