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Abstract Propargylic ethers serve as useful intermediates for the synthesis of a variety of complex targets. However, propargylic substitution of prefunctionalized alkyne starting materials remains the dominant method for the synthesis of propargyl ethers, while direct etherification of simple alkynes via propargylic C−H functionalization remains largely underreported. Herein, we report an organometallic umpolung approach for iron‐mediated C−H propargylic etherification. A telescopic protocol for iron‐mediated C−H deprotonation followed by mild oxidative coupling with alcohols enabled the use of simple or functionalized alkynes for the expedient synthesis of propargylic ethers with excellent functional group compatibility, chemoselectivity and regioselectivity.
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An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes
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.
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- Award ID(s):
- 2016137
- PAR ID:
- 10312454
- Date Published:
- Journal Name:
- Journal of the American Chemical Society
- ISSN:
- 0002-7863
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/jacs.1c11340
