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BIOCATALYSIS Biocatalytic Friedel–Crafts alkylation Angew. Chem. Int. Ed. https://go.nature.com/2EvberW (2019).

Resorcinolsubstrate Alkyl halide electrophile Biocatalytic R2 * R3 Friedel–Crafts alkylation HO OH X=Cl, Br, I EnzymeCylK HO OH Enantioselective + R R 2 3 Regioselective Mildconditions Promiscuous R1 X R1

The Friedel–Crafts alkylation is widely used the wild-type enzyme is limited to arenes in organic chemistry for alkylation of arenes that contain a resorcinol moiety — which is and heteroarenes. However, many Friedel– also found in the natural substrate. However, Crafts alkylation reactions in organic the enzyme tolerated the introduction chemistry face limitations and challenges of diverse functional groups at position concerning regioselectivity, stereoselectivity 4 and 5 of the aromatic ring. Furthermore, and unwanted polyalkylation. Most the authors showed that CylK can also use importantly, the regioselectivity in this secondary alkyl bromides and iodides as reaction commonly originates from the alkylating agents, rather than being limited nature of the arene nucleophile, restricting to secondary alkyl chlorides. the synthetic variability of classical Importantly, the enzyme specifically Friedel–Crafts alkylation reactions. mediates alkylations at the 2-position of Thus, a biocatalytic Friedel–Crafts the resorcinol ring — a substitution found alkylation reaction is desired whereby in many bioactive compounds — whereas the enzyme allows alternative control the classical Friedel–Crafts reaction favours over regioselectivity and stereoselectivity. alkylation at the 4-position. In addition, However, common biocatalytic Friedel– the enzyme performs the reaction in a Crafts reactions require the use of alkylating stereospecific and stereoselective manner. agents that are not prevalent in organic Overall, this work confirms that CylK is a chemistry labs. promising enzyme for organic chemistry. It Recently, a team led by Emily P. Balskus offers several desired synthetic features, and at Harvard University discovered that the the wild-type enzyme shows a good degree enzyme CylK employs a secondary alkyl of promiscuity. Mechanistic and structural chloride — commonly used by organic studies as well as directed evolution are chemists in these reactions — as an anticipated to expand the utility of this alkylating agent for Friedel–Crafts reactions enzyme and the understanding of its in nature. However, the substrate scope catalytic mode. concerning non-native substrates of this enzyme remained unclear. Jan-Stefan Völler Now, Balskus and co-workers expand their work by exploring the substrate scope Published online: 13 March 2019 of wild-type CylK. The results indicate that https://doi.org/10.1038/s41929-019-0262-2

180 Nature Catalysis | VOL 2 | MARCH 2019 | 180 | www.nature.com/natcatal