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ToolsHems, Edward S., Wright, Joseph, Nepogodiev, Sergey A., Devine, Rebecca, Arnold, Corinne J., Hughes, David L., Mundy, Julia E. A., Eltschkner, Sandra, Lawson, David M., Hutchings, Matthew I. and Wilkinson, Barrie (2026) Using X-ray Crystallography and 1,n-ADEQUATE NMR to Revise the Structures of Highly Substituted Aromatic Natural Products: The Absolute Configuration of Formicamycin Congeners. Journal of Natural Products. ISSN 0163-3864
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Abstract
Formicamycins and their biosynthetic precursors, the fasamycins, form part of the phenylnaphthacenoid family of polyketide natural products. A recent atroposelective total synthesis of formicamycin H brought into question our original stereochemical assignment of the axially chiral linkage between C-6 and C7. To address this, we obtained an Xray crystal structure for formicamycin H that unambiguously confirmed our original assignment as the Sa atropisomer. X-ray structures for multiple additional fasamycins and formicamycins confirmed that this is common to all congeners. However, these studies identified a compounded error made by us whereby several structures previously reported as para-methoxy were found to have ortho-methoxy groups on the hanging E-ring.To address this for congeners that did not crystallize or gave nondiffracting crystals, we turned to the surprisingly underutilized 1,n-ADEQUATE NMR experiment. In total, we generated X-ray structures for 15 phenylnaphthacenoid metabolites and by combining these results report the corrected structures for three formicamycins, six fasamycins, and three biosynthetic lactone intermediates, noting that several revised fasamycin structures now match previously reported naphthacemycins. Our results highlight the utility of 1,n-ADEQUATE experiments for regiochemical determination in polysubstituted aromatic molecules. Moreover, our investigations uncovered a potential deracemization step during biosynthesis of the ormicamycin framework.
| Item Type: | Article |
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| Additional Information: | Data Availability: Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC; www.ccdc.cam.ac.uk), and relevant deposition codes are provided in the Experimental Section. The raw NMR data have been deposited in the Natural Products Magnetic Resonance Database (NP-MRD; www.np-mrd.org) and can be found at NP0016596 (formicamycin H (1)); NP0352156 (fasamycin C/napthacemycin B2 (17)), NP0352157 (fasamycin E/napthacemycin B7 (7)), NP0352158 (fasamycin L/napthacemycin B11 (8)), NP0352159 (fasamycin Q/napthacemycin B12 (21)), NP0352160 (lactone intermediate F (25)), NP0352161 (fasamycin M (9)), NP0352162 (fasamycin N (20)), NP0352163 (formicamycin B (15)), NP0352164 (formicamycin D (16)), NP0352165 (formicamycin I (3)), NP0352166 (formicamycin R (5)), NP0352167 (lactone intermediate A (11)), NP0352168 (lactone intermediate B (12)), and NP0352169 (lactone intermediate D (22)). All other data are provided within the body of the manuscript or associated electronic Supporting Information. Requests for materials should be addressed to the corresponding authors. |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Biological Sciences |
| Depositing User: | LivePure Connector |
| Date Deposited: | 12 May 2026 14:30 |
| Last Modified: | 14 May 2026 15:15 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/102965 |
| DOI: | 10.1021/acs.jnatprod.6c00145 |
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