The Friedel‐Crafts alkylation constitutes one of the most important reactions for the formation of carbon‐carbon bonds. Here, we report the Friedel‐Crafts alkylation using squalene‐hopene cyclases, which provides a biological alternative to the traditional strategy. The squalene‐hopene cyclase from Alicyclobacillus acidocaldarius (AacSHC) and variants have been demonstrated to have a broad substrate and reaction scope, making them valuable for potential applications in biocatalysis. Notably, the Friedel‐Crafts alkylation of the substrate geranyl phenyl ether was found to be highly regioselective. Furthermore, squalene‐hopene cyclases exhibit promiscuous activity in catalyzing the hydration of geranyl phenyl ether in an aqueous buffer. Finally, we have analyzed the roles of various active‐site residues and studied their influence on the reaction and product specificity. These findings highlight the promise of enzymatic catalysis for enabling selective C−C bond formations.
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