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Biocatalytic, Intermolecular C-H Bond Functionalization for the Synthesis of Enantioenriched Amides.

ABSTRACT: Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C-N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C-H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate-determining nitrenoid formation followed by stepwise hydrogen atom transfer-mediated C-H functionalization.

SUBMITTER: Athavale SV

PROVIDER: S-EPMC8578410 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Biocatalytic, Intermolecular C-H Bond Functionalization for the Synthesis of Enantioenriched Amides.

Athavale Soumitra V SV Gao Shilong S Liu Zhen Z Mallojjala Sharath Chandra SC Hirschi Jennifer S JS Arnold Frances H FH

Angewandte Chemie (International ed. in English) 20211013 47

Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C-N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C-H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic comp ...[more]

PMID: 34534409

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