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An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

ABSTRACT: Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp³)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is efficient and selective (up to 2610 total turnover number (TTN) and 96% ee) and can be performed on preparative scale.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8765727 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

Liu Zhen Z Qin Zi-Yang ZY Zhu Ledong L Athavale Soumitra V SV Sengupta Arkajyoti A Jia Zhi-Jun ZJ Garcia-Borràs Marc M Houk K N KN Arnold Frances H FH

Journal of the American Chemical Society 20211223 1

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp<sup>3</sup>)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene pr ...[more]

PMID: 34941252

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