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Engineered Enzymes Enable Selective N ‐Alkylation of Pyrazoles With Simple Haloalkanes
Author(s) -
Bengel Ludwig L.,
Aberle Benjamin,
EglerKemmerer AlexanderN.,
Kienzle Samuel,
Hauer Bernhard,
Hammer Stephan C.
Publication year - 2021
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.202014239
Subject(s) - pyrazole , alkylation , chemistry , enzyme , regioselectivity , combinatorial chemistry , cofactor , substrate (aquarium) , biocatalysis , stereochemistry , catalysis , organic chemistry , reaction mechanism , biology , ecology
Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst‐controlled pyrazole alkylation by a cyclic two‐enzyme cascade. In this enzymatic system, a promiscuous enzyme uses haloalkanes as precursors to generate non‐natural analogs of the common cosubstrate S‐adenosyl‐ l ‐methionine. A second engineered enzyme transfers the alkyl group in highly selective C−N bond formations to the pyrazole substrate. The cosubstrate is recycled and only used in catalytic amounts. Key is a computational enzyme‐library design tool that converted a promiscuous methyltransferase into a small enzyme family of pyrazole‐alkylating enzymes in one round of mutagenesis and screening. With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale.