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DOI: 10.1039/A802865F (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 2, 1998, 1947-1956

Solution structures of the 9-ketone and 9,12-hemiacetal forms of erythromycin A in 90% H2O as determined by NMR and molecular modelling

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Fernando Commodari, George E. Sclavos, Abdesslem Khiat and Yvan Boulanger

Abstract

The one-dimensional proton NMR spectrum of an aqueous solution (90% H2O, 10% 2H2O, in phosphate buffer, pH 7.0) of 10 mM erythromycin A is assigned using double quantum filtered correlation spectroscopy (DQFCOSY) and total correlation spectroscopy (TOCSY) spectra. These assignments are then used to determine spatial relationships between the protons obtained from the rotating-frame Overhauser enhancement spectroscopy (ROESY) spectrum. Molecular modelling, with the NMR derived NOE distance constraints from the ROESY spectrum, is used to determine the solution structures of the 9-ketone and the 9,12-hemiacetal forms of the compound. The structure obtained for the ketone is consistent with previous studies (in other solvents), except for some interesting variations in the sugar moieties. For both the 9-ketone and 9,12-hemiacetal, the aglycone ring is found to be primarily ‘folded out’, in a fully staggered Perun type conformation and the sugar moieties are all found to be in the boat conformation and parallel up at the 3 and 5 aglycone ring positions. This study is the first to provide a solution structure for the hemiacetal, which is found to be in equilibrium with the ketone, and the first to look at erythromycin A and its 9,12-hemiacetal tautomer in 90% H2O at physiological pH. The ratio of 9-ketone to 9,12-hemiacetal is found to be 5∶1. Peaks for the 6,9-hemiacetal are observed at very low intensity.

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