Research ArticleChemistry

Direct N-alkylation of unprotected amino acids with alcohols

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Science Advances  08 Dec 2017:
Vol. 3, no. 12, eaao6494
DOI: 10.1126/sciadv.aao6494
  • Fig. 1 Sustainable catalytic methods for the synthesis of N-alkyl amino acids and areas of application.

    (A) Fossil versus renewable pathways to value-added amines. The nonrenewable path proceeds via the Haber-Bosch process and uses petrochemicals as reaction partners to obtain simple amines, which are further functionalized. The alternative pathway uses natural amino acids, which are directly coupled with alcohols derived from renewable resources to obtain fully bio-based N-alkyl amino acids. The fundamental challenge is the development of efficient and sustainable catalytic methods to enable this step. ee, enantiomeric excess. (B) Various areas of application of N-alkyl amino acids.

  • Fig. 2 Classical strategies versus sustainable pathways for N-alkylation of unprotected amino acids.

    (A) Classical methods for the N-alkylation of α-amino acids. (B) Sustainable, waste-free direct coupling of α-amino acids with alcohols. (C) Proposed mechanism of the direct N-alkylation of α-amino acids with alcohols via the “borrowing hydrogen” strategy.

  • Fig. 3 N-alkylation of amino acids and N-terminal modification of peptides with various alcohols.

    See the General procedure in Materials and Methods for the description of the experimental procedure and tables S2 to S5 for further details on these experiments. General reaction conditions: 0.2 mmol of 1, 1 to 5 ml or 0.6 to 2 mmol of 2, 1 mol % Cat 1, neat when using ethanol (2a), 1 ml of CF3CH2OH (2d) when using iPrOH (2b), 18 to 47 hours, and 90°C unless otherwise specified. Isolated yields are shown, and the ee of the product was measured by high-performance liquid chromatography (HPLC) upon established derivatization procedures (see Determination of the optical purity of products in the Supplementary Materials). #Neat; ^CF3CH2OH was used as solvent; a2 mol % Cat 1 was used; b100°C.

  • Fig. 4 Synthesis of bio-derived surfactant.

    (A) Conventional stoichiometric pathways for synthesizing amino acid–based surfactants. (B) Novel, catalytic method for the direct N-alkylation of amino acids with fatty alcohols with a well-defined iron catalyst, using alcohols of various lengths and cyclic and acyclic amino acids, to provide amino acid–based surfactants after the addition of aqueous KOH. See General procedure in Materials and Methods for the description of the experimental procedure and table S6 for further details on these experiments. General reaction conditions: 0.5 mmol of 1, 1 ml or 2 mmol of 2, neat or CF3CH2OH (2d) as solvent, 5 mol % Cat 2, 18 to 42 hours, and 110°C. Isolated yields are shown. aThe corresponding methyl esters were isolated. TMS, tetramethylsilane.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/12/eaao6494/DC1

    table S1. Optimization of reaction conditions for the direct N-ethylation of unprotected amino acids (1a to 1i) with ethanol (2a).

    table S2. Direct mono-N-isopropylation of an amino acid (1) with isopropanol (2b).

    table S3. Direct N-alkylation of a free amino acid (1) with various alcohols (2).

    table S4. Direct N-alkylation of di- and tripeptides (4a to 4b) with alcohols (2).

    table S5. Iron-catalyzed N-ethylation of amino acids with ethanol (2a).

    table S6. Iron-catalyzed N-alkylation of unprotected amino acids (1a to 1c) with long-chain aliphatic alcohols (2) to produce surfactants.

    Spectral data of isolated compounds

    Determination of the optical purity of products

    HPLC traces

    1H and 13C NMR spectra

    References (3345)

  • Supplementary Materials

    This PDF file includes:

    • table S1. Optimization of reaction conditions for the direct N-ethylation of unprotected amino acids (1a to 1i) with ethanol (2a).
    • table S2. Direct mono-N-isopropylation of an amino acid (1) with isopropanol (2b).
    • table S3. Direct N-alkylation of a free amino acid (1) with various alcohols (2).
    • table S4. Direct N-alkylation of di- and tripeptides (4a to 4b) with alcohols (2).
    • table S5. Iron-catalyzed N-ethylation of amino acids with ethanol (2a).
    • table S6. Iron-catalyzed N-alkylation of unprotected amino acids (1a to 1c) with long-chain aliphatic alcohols (2) to produce surfactants.
    • Spectral data of isolated compounds
    • Determination of the optical purity of products
    • HPLC traces
    • 1H and 13C NMR spectra
    • References (33–45)

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