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Rapid Cleavage of Unactivated, Unstrained Amide Bonds at Neutral pH

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    Rapid Cleavage of Unactivated, Unstrained Amide Bonds at Neutral pH
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    Department of Chemistry, Amherst College, Amherst, Massachusetts 01002, and Laboratoire de Chimie Organique, Photochimie et Synthèse, Université de Lyon CNRS, ICBMS UMR 5246, 43 boulevard du 11 novembre 1918, Villeurbanne, F-69622, France
    [email protected]
    †Amherst College.
    ‡Université de Lyon.
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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2008, 73, 16, 6413–6416
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    https://doi.org/10.1021/jo800706y
    Published July 10, 2008
    Copyright © 2008 American Chemical Society
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    Abstract

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    Building upon the discovery of Suggs and Pires that N-(2-hydroxyethyl)glycine amides undergo rapid amide cleavage under mild conditions [Suggs, J. W.; Pires, R. M. Tetrahedron Lett.1997, 38, 2227–2230], we synthesized the derivatives (4aα,8β,8aα)-1-ethylamido-8-hydroxydecahydroquinoline (4) and (4aα,8α,8aβ)-1-ethylamido-8-hydroxydecahydroquinoline (5). These two species are conformationally constrained, but steric compression is not introduced between the hydroxyl group and the amide functionality it attacks. At 20 °C and slightly basic pH, derivatives 4 and 5 undergo amide cleavage with half-lives of 21 min and 14 h, respectively, which correspond to rate increases of 251- and 6.3-fold relative to the acyclic analogue N-(2-hydroxyethyl)glycine amide (3).

    Copyright © 2008 American Chemical Society

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    Supporting Information

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    1H and 13C NMR spectra of compounds 4 and 5; 1H NMR spectrum of the mixture of diastereomers 6−9obtained from the reduction of 8-hydroxyquinoline; expansions of the 1H NMR multiplets for H8 in compounds 6−9; 1H NMR, 13C NMR, and IR spectra of compounds 6 and 7; a tabulation of the spectral data, including HRMS, for compounds 4−7; a table of the rate constants for amide cleavage at each pD for compounds 2, 4, and 5; and the details of the molecular mechanics calculations. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 6 publications.

    1. Chenikkayala Balachandra and Nagendra K. Sharma . Instability of Amide Bond Comprising the 2-Aminotropone Moiety: Cleavable under Mild Acidic Conditions. Organic Letters 2015, 17 (16) , 3948-3951. https://doi.org/10.1021/acs.orglett.5b01535
    2. Fei Shen, Zhi-Ping Zhang, Jia-Bin Li, Yun Lin, and Lei Liu . Hydrazine-Sensitive Thiol Protecting Group for Peptide and Protein Chemistry. Organic Letters 2011, 13 (4) , 568-571. https://doi.org/10.1021/ol1028755
    3. Karthick Govindan, Nian-Qi Chen, Hsing-Yin Chen, Sodio C. N. Hsu, Wei-Yu Lin. The copper-catalyzed oxidative radical process of site selective C–N bond cleavage in twisted amides: batch and continuous-flow chemistry. Catalysis Science & Technology 2023, 13 (6) , 1633-1639. https://doi.org/10.1039/D2CY02063G
    4. Igor V. Komarov, Aleksandr Yu. Ishchenko, Aleksandr Hovtvianitsa, Viacheslav Stepanenko, Serhii Kharchenko, Andrew D. Bond, Anthony J. Kirby. Fast Amide Bond Cleavage Assisted by a Secondary Amino and a Carboxyl Group—A Model for yet Unknown Peptidases?. Molecules 2019, 24 (3) , 572. https://doi.org/10.3390/molecules24030572
    5. Fabienne Burlina, George Papageorgiou, Caroline Morris, Peter D. White, John Offer. Insitu thioester formation for protein ligation using α-methylcysteine. Chem. Sci. 2014, 5 (2) , 766-770. https://doi.org/10.1039/C3SC52140K
    6. John L. Murphy, William J. Tenn, Joseph J. Labuda, Richard W. Nagorski. Rapid amidic hydrolysis: a competitive reaction pathway under basic conditions for N-(hydroxymethyl)benzamide derivatives bearing electron-donating groups. Tetrahedron Letters 2009, 50 (52) , 7358-7361. https://doi.org/10.1016/j.tetlet.2009.10.069
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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2008, 73, 16, 6413–6416
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jo800706y
    Published July 10, 2008
    Copyright © 2008 American Chemical Society
    Request reuse permissions

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