Synthesis, NMR and X-ray structure analysis of macrolide aglycons

Macrolide aglycons ( E )-9-hydroxyimino-6- O -methylerythronolide A ( 4 ), 9a-aza-9-deoxo-9,9-dihydro-9a,11- O -dimethyl-9a-homoerythronolide A ( 5 ) and 9a-aza-9-deoxo-9,9-dihydro-9a-homoerythronolide A ( 6 ) were prepared by multistep syntheses. A conformational study of these new macrolide aglycons was performed using single crystal X-ray crystallography to gain information about the solid state, while a combination of NMR spectroscopy and molecular modelling was employed to study the solution structures. The crystal structures were found to be stabilised by a complex network of hydrogen bonds and van der Waals interactions. To some extent, the same building motif of infinite molecular chains held together by O–H···O hydrogen bonds was present in the crystal structure of all three compounds. Thorough analysis and comparison of the obtained solid state structures with their solution counterparts showed no significant differences between them, confirming the constrained flexibility of the macrocyclic ring. Moreover, in all three compounds, in both solution and solid state, the macrolactone ring adopts energetically more favoured folded-out conformations.