Organic Chemistry

Structure Revision of the Lomaiviticins


The lomaiviticins are dimeric genotoxic bacterial 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 non-trivial. 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-en-1-one. The bridging bond was positioned at C6. This structure proposal has not been tested because none of the lomaiviticins have been prepared by total chemical synthesis or (to the best of our knowledge) successfully analyzed by X-ray crystallography. Here we disclose microED studies which establish that (–)-lomaiviticin C contains a 4,6-dihydroxy-cyclohex-2-en-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 fortuitous combination of a nearzero 3JH4,H5 coupling constant and a 4-bond HMBC correlation that was interpreted as a 3-bond coupling. DFT calculations of the expected 13C chemical shifts of the original and revised structures of the aglycon and (–)-lomaiviticin B 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 products structure determination.


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