Structure Revision of the Lomaiviticins

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.

Files

Additional details