The conformational analysis of erythromycin A

Abstract

¹ H and ¹³C n.m.r. spectroscopy combined with molecular modelling techniques were used to show that the major conformation of erythromycin A (1) in CDCl₃ solution is very similar to the crystalline state conformation (A) of erythromycin A hydroiodide dihydrate. However, ¹H nuclear Overhauser enhancement (n.O.e.), variable-temperature and variable-solvent n.m.r. experiments showed that, in contrast to previous reports, the major conformation of (1) is in fast equilibrium with a second, minor conformation. This minor conformation is related to the major conformation via a reorganisation of the macrocyclic lactone ring in the C-2 to C-9 region.

¹³ C N.m.r. relaxation measurements showed that the desosamine sugar possesses more conformational freedom than the cladinose sugar, in agreement both with previous results and with energy calculations based on the crystal structure. In addition, the relaxation experiments indicated that some methyl groups in (1) are sterically hindered whereas others possess motional freedom. A good agreement was found between the n.m.r. relaxation results and calculations of methyl group rotational energy barriers in the crystal structure. This good agreement provided further evidence of the similarity between the major solution-state conformation of (1) and the crystalline-state conformation A.