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Wheldone Revisited: Structure Revision via DFT-GIAO chemical shift calculations, 1,1-HD-ADEQUATE NMR Spectroscopy, and X-ray Crystallography Studies

Lookup NU author(s): Dr Kin Lok Ho, Alexandra Longcake, Dr Michael HallORCiD, Professor Mike ProbertORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Wheldone was reported recently as a fungal metabolite isolated from the co-culture of Aspergillus fischeri and Xylaria flabelliformis, and it displayed cytotoxic activity against breast, melanoma, and ovarian cancer cell lines. Initially, its structure was characterized as an unusual 5-methyl-bicyclo[5.4.0]undec-3,5-diene scaffold with a 2‑hydroxy-1-propanone side chain and a 3-(2-(1-hydroxyethyl)-2-methyl-2,5-dihydrofuran-3-yl)acrylic acid moiety. Upon further examination, minor inconsistencies in the data suggested the need for structural revision. Thus, the structure of wheldone has been revisited herein using an orthogonal experimental-computational approach, which combines 1,1-HD-ADEQUATE NMR experiments, DFT-GIAO chemical shift calculations, and single crystal X-ray diffraction (SCXRD) analysis of a semi-synthetic p‑bromobenzylamide derivative, formed via a Steglich-type reaction. The summation of these data, in conjunction with previously reported Mosher’s ester analysis, now permit the unequivocal assignment of both the structure and absolute configuration of the natural product.


Publication metadata

Author(s): Rangel-Grimaldo M, Earp CE, Raja HA, Wood JS, Crull EB, Mardiana L, Ho KL, Longcake A, Williamson RT, Palatinus L, Hall MJ, Probert MR, Oberlies NH

Publication type: Article

Publication status: Published

Journal: Journal of Natural Products

Year: 2024

Volume: 87

Issue: 8

Pages: 2095-2100

Print publication date: 23/08/2024

Online publication date: 23/07/2024

Acceptance date: 11/07/2024

Date deposited: 05/08/2024

ISSN (print): 0163-3864

ISSN (electronic): 1520-6025

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acs.jnatprod.4c00649

DOI: 10.1021/acs.jnatprod.4c00649

Data Access Statement: The NMR data for wheldone have been deposited in the Natural Products Magnetic Resonance Database (NP-MRD; www.np_mrd.org) and can be found at NP0021048. Also, CCDC 2330603 contains the supplementary crystallographic data for this paper, and 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:+441223336033.


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Funding

Funder referenceFunder name
EP/W021129/1
EPSRC
MR/T000740/1Medical Research Council (MRC)
National Institutes of Health, National Cancer Institute via P01 CA125066
National Science Foundation (NSF; Grant ECCS-2025462)
NSF grants 0821552 and 2116395
Universitas Indonesia

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