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Article

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Publicated to:Journal Of The American Chemical Society. 145 (2): 787-793 - 2023-01-06 145(2), DOI: 10.1021/jacs.2c12197

Authors: Fu H; Qiao T; Carceller JM; MacMillan SN; Hyster TK

Affiliations

Cornell Univ, Dept Chem & Chem Biol - Author
Univ Politecn Valencia, Inst Chem Technol ITQ - Author

Abstract

Tertiary nitroalkanes and the corresponding alpha-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemoand stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent ene-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzymetemplated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Keywords

AlkaneAlkanesAlkylationAlpha-tertiary aminesAminesAnionsArticleAsymmetric synthesisBioactive moleculesBiocatalysisC alkylationC-alkylationCatalysisCharge transferChemical phenomenaChemical structureChemistryChemoselectiveChemoselectivityControlled studyDirected evolutionDiscoveryElectrophilesEnantioselective synthesisEnantioselectivityEnereductaseEnzyme substrateEnzymesGeobacillusGeobacillus kaustophilusHalideMechanismMichael additionMolecular evolutionNatural productsNitro compoundsNitro derivativeNitroalkaneNitroalkane derivativeNitroalkanesOxidation reduction reactionOxidoreductaseParaffinsPhotocatalysisPhotoredox catalysisQuercetinRadical cyclizationRecombinant enzymeReductionStereo-selectiveStereoselectivityStraightforward strategyTertiary amineUnclassified drugX ray crystallography

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of The American Chemical Society due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 18/231, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Multidisciplinary. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.2. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 5.53 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 14.71 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-22, the following number of citations:

  • WoS: 28
  • Scopus: 42
  • OpenCitations: 31

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-22:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 46.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 46 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 22.1.
  • The number of mentions on the social network X (formerly Twitter): 22 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.