Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 18;145(2):787-793.
doi: 10.1021/jacs.2c12197. Epub 2023 Jan 6.

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Haigen Fu  1 , Tianzhang Qiao  1 , Jose M Carceller  1   2 , Samantha N MacMillan  1 , Todd K Hyster  1
Affiliations

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Haigen Fu et al. J Am Chem Soc. .

Abstract

Tertiary nitroalkanes and the corresponding α-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 chemo- and 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 enzyme-templated 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.

PubMed Disclaimer

Figures

Figure. 1.
Figure. 1.
Photoenzymatic asymmetric C-alkylation of nitroalkanes. (A) Selected examples of bioactive molecules containing α-tertiary amine or nitroalkane motifs. (B) Proposed photoenzymatic C-alkylation of nitroalkanes. (C) GkOYE-catalyzed model reaction. a Standard condition: 1a (10 μmol, 1 equiv), 2a (20 μmol, 2 equiv), GkOYE (1 mol%) in Tricine buffer (100 mM, pH 9.0), 10% DMSO, cyan LED, rt, 24 h. b Yield determined via LCMS relative to an internal standard 1,3,5-tribromobenzene. c er (R:S) determined by HPLC on a chiral stationary phase. d not determined. e Condition see SI Table 1.
Figure 2.
Figure 2.
Protein engineering. The crystal structure of wild-type GkOYE (PDB: 3GR8) with three beneficial mutations is shown, 0.5 mol% GkOYE variants were used.
Figure. 3.
Figure. 3.
Substrate scope. The absolute R-configuration of product 3a, 15 and 22 were assigned by X-ray crystallography, other products were tentatively assigned the R-configuration based on analogy. a Analytical reactions were performed on a 10 μmol scale,isolated yields of 0.10 mmol-scale reaction were reported in parentheses. b Absolute configuration not determined. c CsER (0.75 mol%) and α-bromo ester or sulfone were used.
Figure 4.
Figure 4.
Enzyme-controlled reactivity. Reaction conditions: nitroalkane (10 μmol, 1 equiv), 1a (20 μmol, 2 equiv), GDH-105 (0.6 mg), NADP+ (0.1 μmol, 1 mol%), glucose (50 μmol) and ‘ene’-reductases (0.1 μmol, 1 mol%) in Tricine buffer (100 mM, pH 9.0), 10% DMSO, cyan LED, rt, 24 h. The absolute S-configuration of 43a was assigned by X-ray crystallography (SI Table 8), 39a–42a were tentatively assigned the S-configuration based on analogy. The absolute S-configuration of products 39b–43b were assigned previously.
Figure 5.
Figure 5.
Enzymatic cascade reaction and product derivatization. a Conditions see general procedure 5 in SI.
Figure 6.
Figure 6.
Mechanistic experiments.
See this image and copyright information in PMC

References

    1. Hager A; Vrielink N; Hager D; Lefranc J; Trauner D Synthetic Approaches towards Alkaloids Bearing α-Tertiary Amines. Nat. Prod. Rep. 2016, 33, 491–522. - PubMed
    2. Clayden J; Donnard M; Lefranc J; Tetlow DJ Quaternary Centres Bearing Nitrogen (α-Tertiary Amines) as Products of Molecular Rearrangements. Chem. Commun. 2011, 47, 4624–4639. - PubMed
    3. Hoffmann-La Roche AG. Pyridine-2-amides Useful as CB2 Agonists.WO2014086805. 2014.
    4. Parry R; Nishino S; Spain J Naturally-Occurring Nitro Compounds. Nat. Prod. Rep. 2010, 28, 152–167. - PubMed
    1. Stereoselective Formation of Amines; Li W; Zhang X, Eds; Springer: Berlin, 2014.
    2. Shibasaki M; Kanai M Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C─C Bond Formation to Ketones and Ketimines. Chem. Rev. 2008, 108, 2853–2873. - PubMed
    3. Robak MT; Herbage MA; Ellman JA Synthesis and Applications of Tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600–3740. - PubMed
    4. Yus M; Gonzalez-Gomez JC; Foubelo F Catalytic Enantioselective Allylation of Carbonyl Compounds and Imines. Chem. Rev. 2011, 111, 7774–7854. - PubMed
    5. Guo T; Song R; Hua Yuan B; Yang Chen X; Sun XW; Qiang Lin G Highly Efficient Asymmetric Construction of Quaternary Carbon-Containing Homoallylic and Homopropargylic Amines. Chem. Commun. 2013, 49, 5402–5404. - PubMed
    6. Wu Y; Hu L; Li Z; Deng L Catalytic Asymmetric Umpolung Reactions of Imines. Nature 2015, 523, 445–450. - PMC - PubMed
    7. Bahamonde A; Al Rifaie B; Martín-Heras V; Allen JR; Sigman MS Enantioselective Markovnikov Addition of Carbamates to Allylic Alcohols for the Construction of α-Secondary and α-Tertiary Amines. J. Am. Chem. Soc. 2019, 141, 8708–8711. - PMC - PubMed
    8. Fager DC; Yan R; Morrison J; Hoveyda AH Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic α-Tertiary NH2-Amines by Reactions Facilitated by a Threonine-Based Boron-Containing Catalyst. Angew. Chem. Int. Ed. 2020, 59, 11448–1145. - PMC - PubMed
    9. Gao X; Turek-Herman JR; Choi YJ; Cohen RD; Hyster TK Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent “Ene”-Reductases. J. Am. Chem. Soc. 2021, 143, 19643–19647. - PMC - PubMed
    1. Maki K; Kanai M; Shibasaki M Pd-Catalyzed Allylic Alkylation of Secondary Nitroalkanes. Tetrahedron 2007, 63, 4250–4257.
    2. Ohmatsu K; Ito M; Kunieda T; Ooi T Ion-Paired Chiral Ligands for Asymmetric Palladium Catalysis. Nat. Chem.2012, 4, 473–477. - PubMed
    3. Trost BM; Schultz JE; Bai Y Development of Chemo- and Enantioselective Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of α-Nitroesters. Angew. Chemie Int. Ed. 2019, 58, 11820–11825. - PubMed
    4. Davison RT; Parker PD; Hou X; Chung CP; Augustine SA; Dong VM Enantioselective Addition of α-Nitroesters to Alkynes. Angew. Chemie Int. Ed. 2021, 60, 4599–4603. - PMC - PubMed
    5. Latvala A; Stanchev S; Linden A; Hesse M Unexpected Change of Absolute Configuration in Asymmetric Michael Addition of Methyl Vinyl Ketone to 2-Nitrocycloalkanones. Tetrahedron Asymmetry 1993, 4, 173–176.
    6. Knudsen KR; Jørgensen KA A Chiral Molecular Recognition Approach to the Formation of Optically Active Quaternary Centres in Aza-Henry Reactions. Org. Biomol. Chem. 2005, 3, 1362–1364. - PubMed
    7. Prakash GKS; Wang F; Stewart T; Mathew T; Olah GA α-Fluoro-α-Nitro(Phenylsulfonyl)Methane as a Fluoromethyl Pronucleophile: Efficient Stereoselective Michael Addition to Chalcones. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 4090–4094. - PMC - PubMed
    8. Vara BA; Johnston JN Enantioselective Synthesis of β-Fluoro Amines via β-Amino α-Fluoro Nitroalkanes and a Traceless Activating Group Strategy. J. Am. Chem. Soc. 2016, 138, 13794–13797. - PMC - PubMed
    9. Singh A; Johnston JN A Diastereo-and Enantioselective Synthesis of α-Substituted Syn-α,β-Diamino Acids. J. Am. Chem. Soc 2008, 130, 5866–5867. - PubMed
    10. Bing JA; Schley ND; Johnston JN Fluorine-Induced Diastereodivergence Discovered in an Equally Rare Enantioselective Syn-Aza-Henry Reaction. Chem. Sci, 2022, 13, 2614–2623. - PMC - PubMed
    1. Hass HB; Bender ML The Reaction of Benzyl Halides with the Sodium Salt of 2-Nitropropane. A General Synthesis of Substituted Benzaldehydes. J. Am. Chem. Soc. 1949, 71, 1767–1769.
    1. Kornblum N; Michel RE; Kerber RC Radical Anions as Intermediates in Substitution Reactions. J. Am. Chem. Soc. 1966, 88, 5660–5662.
    2. Katritzky AR; Kashmiri MA; de Ville GZ; Patel RC Kinetics and Mechanism of the C-Alkylation of Nitroalkane Anions by l-Alkyl-2,4,6-Triphenylpyridiniums: A Nonchain Reaction with Radicaloid Characteristics. J. Am. Chem. Soc. 1983, 105, 90–96.

Publication types