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Structure Revision of the Lomaiviticins

Kim, Lee Joon and Xue, Mengzhao and Li, Xin and Xu, Zhi and Paulson, Eric and Mercado, Brandon and Nelson, Hosea M. and Herzon, Seth B. (2021) Structure Revision of the Lomaiviticins. Journal of the American Chemical Society, 143 (17). pp. 6578-6585. ISSN 0002-7863. doi:10.1021/jacs.1c01729. https://resolver.caltech.edu/CaltechAUTHORS:20210811-225350804

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Abstract

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 ³J_(H₄,H₅) coupling constant and a ⁴J_(C,H) coupling interpreted as a ³J_(C,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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c01729DOIArticle
https://doi.org/10.26434/chemrxiv.13956122.v1DOIDiscussion Paper
https://cen.acs.org/biological-chemistry/natural-products/Lomaiviticinsstructures-revision/99/i17Featured InC&EN -- Science Concentrates
ORCID:
AuthorORCID
Kim, Lee Joon0000-0002-0786-7614
Paulson, Eric0000-0002-4612-3634
Mercado, Brandon0000-0002-1940-3497
Nelson, Hosea M.0000-0002-4666-2793
Herzon, Seth B.0000-0001-5940-9853
Additional Information:© 2021 American Chemical Society. Received 12 February 2021. Published online 26 April 2021. Published in issue 5 May 2021. The authors thank Duilio Cascio (UCLA-DOE Institute) for assistance in data processing. Financial support from the National Institutes of Health (R35-GM131913 to S.B.H), the David and Lucile Packard Foundation (Fellowship to H.M.N.), Bristol Myers Squibb (Unrestricted Grant in Synthetic Organic Chemistry to H.M.N.), and Yale University is gratefully acknowledged. Author Contributions. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest. 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 data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Funders:
Funding AgencyGrant Number
National Institute of General Medical SciencesR35-GM131913
David and Lucile Packard FoundationUNSPECIFIED
Bristol-Myers SquibbUNSPECIFIED
Yale UniversityUNSPECIFIED
Subject Keywords:Crystal structure, Molecular properties, Chemical structure, Molecular structure, Nuclear magnetic resonance spectroscopy
Issue or Number:17
DOI:10.1021/jacs.1c01729
Record Number:CaltechAUTHORS:20210811-225350804
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210811-225350804
Official Citation:Structure Revision of the Lomaiviticins Lee Joon Kim, Mengzhao Xue, Xin Li, Zhi Xu, Eric Paulson, Brandon Mercado, Hosea M. Nelson, and Seth B. Herzon Journal of the American Chemical Society 2021 143 (17), 6578-6585 DOI: 10.1021/jacs.1c01729
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110205
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:13 Aug 2021 16:59
Last Modified:13 Aug 2021 17:41

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