The structure of velutinol A is (15R,16R,20S)-14,16:15,20:16,21-triepoxy-15,16-seco-14β,17α-pregn-5-ene-3β,15-dioul. A combined quantitative Overhauser effect and molecular modelling study

Abstract

Velutinol A, a potent bradykinin antagonist isolated from the rhizomes of the native Brazilian plant Mandevilla velutina, has been confirmed to have the title structure through the combined use of quantitative-¹H–¹H nuclear Overhauser enhancement (NOE) data and molecular dynamics/energy minimisation calculations. The NOE data allowed the unambiguous selection of the structure from four possible, closely related, isomeric structures. Interproton distances from the NOE data were within 0.5 Å; of those calculated from the optimised model structure for the rigid section of the molecule and within 0.6 Å; when the methyl group was considered. Various models were considered for calculating the effective distance to a methyl group undergoing internal molecular motion. The most successful in reproducing the experimental data was the so-called ‘pseudo-atom’ approach, with a 0.3 Å correction applied to the experimental distances, and the more rigorous Rowan–Woessner approach, which considers the methyl group rotation to be by ±120° jumps between the positions of potential minima. Through the application of field dependent ¹³C relaxation time measurements the correlation times for overall motion of velutinol A and internal motion of the C18 methyl group were found to be 0.34 × 10^–10 and 0.05 × 10^–10 s, respectively. The ¹³C spin-lattice relaxation of the spa carbons is dominated by the ¹³C–¹H dipole–dipole mechanism, however the relaxation time for the sp² carbon C5 is strongly field dependent, and a value of 227 ppm is obtained for the chemical shift anisotropy.