NMR spectroscopic and X-ray crystallographic studies on the structure, stereochemistry and conformation of a series of 9,11-cyclic aminals of (9S)-9-N-methylerythromycylamine A

Abstract

(9S)-9-N-Methylerythromycylamine A (6) and (9S)-9-N,N-dimethylerythromycylamine A (7) have been synthesised and their solution conformations compared with that of (9S)-erythromycylamine A (5) using ¹H and ¹³C NMR spectroscopy. Compound 6 reacts with a number of aliphatic aldehydes to give 9,11-cyclic products which are shown to be diastereoisomeric about the bridging carbon atom C-23. Compounds with the same configuration at C-23 show close similarities in their ¹H and ¹³C NMR spectra. In some cases, configurational interconversion at C-23 occurred by the well known ‘ring-chain’ tautomerism of tetrahydro-1,3-oxazines. The tetrahydro-1,3-oxazine rings of compounds with a (23R) configuration adopt a chair-like conformation while those compounds with a (23S) configuration prefer a twist-boat-like conformation. From NMR spectroscopic studies the solution conformations of the macrocyclic lactones of these compounds is best described as a fast equilibrium between C-3 to C-5 ‘folded out’ and C-3 to C-5 ‘folded-in’ types. Epimerisation at C-23 causes profound changes in the position of this equilibrium:compounds with the (23S) stereochemistry preferentially populate ‘folded-out’ conformations modelled on the crystal structure of erythromycin A hydroiodide dihydrate, while those possessing the (23R) configuration preferentially populate ‘folded-in’ conformational types similar to the crystal structure of (9S),(22R)-9,11 -N,O-(2-methoxyethoxyethylidine)erythromycylamine A (10).

An example of each diastereoisomer at C-23 was chosen for X-ray diffraction studies. The crystal structures of (9S,23S)-9-N-methyl-9,11-N,O-(2-hydroxyethylidene)erythromycylamine A (25) and (9S,23R)-9-N-methyl-9,11-N,O-(3-ethoxypropylidene)erythromycylamine A (28) are thus reported and confirm the structural and conformational conclusions determined by NMR spectroscopy.