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

J S DAVIES, J R EVERETT, I K HATTON, E HUNT, J W TYLER, I I ZOMAYA, A M Z SLAWIN, D J WILLIAMS

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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 H-1 and C-13 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 H-1 and C-13 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.

Original languageEnglish
Pages (from-to)201-214
Number of pages14
JournalJournal of Chemical Society, Perkin Transactions 2
Issue number2
Publication statusPublished - Feb 1991

Keywords

  • RING-CHAIN TAUTOMERISM
  • A CYCLIC CARBONATE
  • ERYTHROMYCIN-A
  • MOLECULAR-STRUCTURE
  • 1,3-OXAZINES
  • HETEROCYCLES
  • DERIVATIVES
  • ACETAL
  • H-1

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