Enzymatic Friedel‐Crafts Alkylation Using Squalene‐Hopene Cyclases

Abstract

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.

Biocatalytic Friedel‐Crafts Reactions

“…[94] A substrate that forms two carbocycles in this process is required for this reaction, and both AacSHC and ZmoSHC show low conversions. [94][95] However, for AacSHC, which has good evolvability, the desired reaction is competed by a undesired hydration process that gives an alcohol product without an aryl-alkyl bond. [95] Screening of a library of 66 AacSHC mutants, mostly at the positions previously described, identified some positions important for both con- B. Unnatural reactions catalysed by AacSHC mutants where the wild-type gives less than 1 % conversion.…”

“…[94][95] However, for AacSHC, which has good evolvability, the desired reaction is competed by a undesired hydration process that gives an alcohol product without an aryl-alkyl bond. [95] Screening of a library of 66 AacSHC mutants, mostly at the positions previously described, identified some positions important for both con- B. Unnatural reactions catalysed by AacSHC mutants where the wild-type gives less than 1 % conversion. [93] C. Friedel-Crafts alkylation and hydration sideproduct by wild-type AacSHC and the best performing double mutant identified.…”

“…[93] C. Friedel-Crafts alkylation and hydration sideproduct by wild-type AacSHC and the best performing double mutant identified. [95] See references for detailed reaction conditions. version as well as product selectivity.…”

“…B. Unnatural reactions catalysed by Aac SHC mutants where the wild‐type gives less than 1 % conversion [93] . C. Friedel‐Crafts alkylation and hydration side‐product by wild‐type Aac SHC and the best performing double mutant identified [95] . See references for detailed reaction conditions.…”

Tailoring the squalene-hopene cyclase for stereoconvergent and efficient cationic cyclization cascades

“…a Friedel-Crafts alkylation or a Prins reaction. [17][18][19] Despite this tremendous progress, one persistent limitation employing cyclases, is the strict double-bond isomerism of the linear precursor that governs the fate of the successive sp 3 stereocenter in the cyclic product (Figure 1A). [8,20,21] As a result, the application requires preceding separation of the E/Z isomeric substrate mixtures, which is tedious and costly.…”