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Biocatalytic Friedel–Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme
Author(s) -
Schultz Erica E.,
Braffman Nathaniel R.,
Luescher Michael U.,
Hager Harry H.,
Balskus Emily P.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201814016
Subject(s) - friedel–crafts reaction , regioselectivity , alkylation , chemistry , stereospecificity , biocatalysis , resorcinol , alkyl , aryl , organic chemistry , catalysis , combinatorial chemistry , stereochemistry , reaction mechanism
The Friedel–Crafts alkylation is commonly used in organic synthesis to form aryl–alkyl C−C linkages. However, this reaction lacks the stereospecificity and regiocontrol of enzymatic catalysis. Here, we describe a stereospecific, biocatalytic Friedel–Crafts alkylation of the 2‐position of resorcinol rings using the cylindrocyclophane biosynthetic enzyme CylK. This regioselectivity is distinct from that of the classical Friedel–Crafts reaction. Numerous secondary alkyl halides are accepted by this enzyme, as are resorcinol rings with a variety of substitution patterns. Finally, we have been able to use this transformation to access novel analogues of the clinical drug candidate benvitimod that are challenging to construct with existing synthetic methods. These findings highlight the promise of enzymatic catalysis for enabling mild and selective C−C bond‐forming synthetic methodology.