The mystery of Ulocladine: Revisiting the structure of an 8-membered lactone antibiotic from Ulocladium lanuginosum.

The synthetic study toward ulocladine, a potent eight-membered antibiotic from Ulocladium lanuginosum embodying an (E)-oxocrotonyl group, is reported. The presented synthetic strategy affords only the Z-isomer, as confirmed by X-ray crystallography. Further investigations of double-bond isomerization, followed by DFT calculations, revealed a substantial energy difference between the E- and Z-isomers, strongly disfavouring the persistence of the E-isomer under standard conditions. The computational predictions were supported experimentally when (E)-ulocladine was observed only under UV irradiation of the Z-isomer at low temperature. The instability of in situ-generated (E)-ulocladine was demonstrated by time-dependent 1H NMR analysis, with 50% depletion observed within 100 min at -50 °C. The observed olefin coupling constant of the E-isomer (J = 20.4 Hz) is perfectly in line with quantum-chemical calculations and differs from the reported value (J = 16 Hz). Synthetic (Z)-ulocladine showed no antibacterial activity under the experimental conditions employed. Collectively, the presented results raise doubts about the originally proposed structure of ulocladine.