Structure Revision of the Lomaiviticins

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 3JH4,H5 coupling constant and a 4JC,H coupling interpreted as a 3JC,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.