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    Structure Revision of the Lomaiviticins
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    • Lee Joon Kim
      Lee Joon Kim
      Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
      More by Lee Joon Kim
    • Mengzhao Xue
      Mengzhao Xue
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
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    • Xin Li
      Xin Li
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
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    • Zhi Xu
      Zhi Xu
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
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    • Eric Paulson
      Eric Paulson
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
      Chemical and Biological Instrumentation Center, Yale University, New Haven, Connecticut 06511, United States
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    • Brandon Mercado
      Brandon Mercado
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
      Chemical and Biological Instrumentation Center, Yale University, New Haven, Connecticut 06511, United States
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    • Hosea M. Nelson*
      Hosea M. Nelson
      Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
      *Email: [email protected]
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      Orcidhttp://orcid.org/0000-0002-4666-2793
    • Seth B. Herzon*
      Seth B. Herzon
      Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
      Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06510, United States
      *Email: [email protected]
      More by Seth B. Herzon
      Orcidhttp://orcid.org/0000-0001-5940-9853
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2021, 143, 17, 6578–6585
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    https://doi.org/10.1021/jacs.1c01729
    Published April 26, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    The lomaiviticins are dimeric genotoxic metabolites that contain unusual diazocyclopentadiene functional groups and 2–4 deoxyglycoside residues. Because only 6 of 19 carbon atoms in the monomeric aglycon unit are proton-attached, their structure determination by NMR spectroscopic analysis is difficult. Prior structure elucidation efforts established that the two halves of the lomaiviticins are joined by a single carbon–carbon bond appended to an oxidized cyclohexenone ring. This ring was believed to comprise a 4,5-dihydroxycyclohex-2-ene-1-one. The bridging bond was positioned at C6. This structure proposal has not been tested because no lomaiviticin has been prepared by total chemical synthesis or successfully analyzed by X-ray crystallography. Here, we disclose microED studies which establish that (−)-lomaiviticin C contains a 4,6-dihydroxy-cyclohex-2-ene-1-one residue, that the bridging carbon–carbon bond is located at C5, and that the orientation of the cyclohexenone ring and configuration of the secondary glycoside are reversed, relative to their original assignment. High-field (800 MHz) NMR analysis supports the revised assignment and suggests earlier efforts were misled by a combination of a near-zero 3JH4,H5 coupling constant and a 4JC,H coupling interpreted as a 3JC,H coupling. DFT calculations of the expected 13C chemical shifts and C–H coupling constants provide further robust support for the structure revision. Because the interconversion of lomaiviticins A, B, and C has been demonstrated, these findings apply to each isolate. These studies clarify the structures of this family of metabolites and underscore the power of microED analysis in natural product structure determination.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c01729

    • Procedures for microED analysis, crystallization methods, and graphical reproductions of NMR spectroscopic data (PDF)

    • Coordinates for structure 6a (PDB)

    • Coordinates for structure 6b (PDB)

    • Coordinates for structure 2a (PDB)

    • Coordinates for structure 2b (PDB)

    • Coordinates for structures 3a and 3b (PDB)

    Accession Codes

    CCDC 2062671 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2021, 143, 17, 6578–6585
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.1c01729
    Published April 26, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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