Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp3)–H Amination

Nature harnesses exquisite enzymatic cascades to construct N-heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral N-heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C...

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Bibliographic Details
Published in:ACS central science 2023-12, Vol.9 (12), p.2333-2338
Main Authors: Qin, Zi-Yang, Gao, Shilong, Zou, Yike, Liu, Zhen, Wang, James B., Houk, Kendall N., Arnold, Frances H.
Format: Article
Language:English
Subjects:
Amination
Amino acids
Azides (organic)
Catalysis
Chemical synthesis
Construction
Cytochrome
Directed evolution
Enantiomers
Enzymes
Evolution
Harnesses
Heterocyclic compounds
Investigations
Mutagenesis
Mutation
Nitrogen
Oxidation
Pyrrolidine
Substrates
Tryptophan
Tryptophan synthase
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Summary:Nature harnesses exquisite enzymatic cascades to construct N-heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral N-heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C­(sp3)–H amination of organic azides. Directed evolution of cytochrome P411 (a P450 enzyme with serine as the heme-ligating residue) yielded variant P411-PYS-5149, capable of catalyzing the insertion of alkyl nitrene into C­(sp3)–H bonds to build pyrrolidine derivatives with good enantioselectivity and catalytic efficiency. Further evolution of activity on aryl azide substrates yielded variant P411-INS-5151 that catalyzes intramolecular C­(sp3)–H amination to afford chiral indolines. In addition, we show that these enzymatic aminations can be coupled with a P411-based carbene transferase or a tryptophan synthase to generate an α-amino lactone or a noncanonical amino acid, respectively, underscoring the power of new-to-nature biocatalysis in complexity-building chemical synthesis.
ISSN:2374-7943
2374-7951
DOI:10.1021/acscentsci.3c00516