The conformational analysis of three derivatives of erythromycin A: (9S)-9-hydroxy-9-deoxoerythromycin A, (9S)-9,11-O-isopropylidene-9-deoxoerythromycin A, and (9S)-erythromycylamine A by nuclear magnetic resonance spectroscopy and molecular modelling

Abstract

The ¹H and ¹³C n.m.r. spectra of (9S)-9-hydroxy-9-deoxoerythromycin A (2), (9S)-9, 11-O-isopropylidene-9-deoxoerythromycin A (3), and (9S)-erythromycylamine A (4) were solved by two-dimensional (2D) n.m.r. methods. The solution conformations of compounds (2), (3), and (4) were then determined by n.m.r. spectroscopy [n.O.e.(1D and 2D) and T₁ experiments] and compared with the solution conformation of erythromycin A (1). In each case the cladinose and desosamine sugars are in the same chair conformations as found in (1). Furthermore the overall orientations of both sugars were found to be very similar to those of (1) in all cases. However, the lactone rings of (2) and (4) were found to be in fast exchange between conformations characterised as ‘folded-in’ or ‘folded-out’ in the C-3 to C-5 region, whereas the lactone ring of (3) was predominantly in a ‘folded-out’ conformation, as was found for (1). The ‘folded-in’ conformations are novel and have not been previously described. Molecular modelling was used in order to compare the solution-state conformations with crystalline-state models of the two types of lactone ring conformation. No simple correlation was found between the solution-state conformational preferences of compounds (1)–(4) and their antibacterial activities.