Modification of macrolide antibiotics. Synthesis of 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic esters) via an intramolecular Michael reaction of O-carbamates with an .alpha.,.beta.-unsaturated ketone

Erythromycin A is the drug of choice for the treatment of Legionnaires' disease, an infection produced by Legionella pneumophila . However, one major limitation to erythromycin A therapy is its short in vivo half-life in humans (2 H). The synthesis of 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic esters) 13 was accomplished in five steps from 6-O-methylerthromycin A in 40% overall yield. The process featured a mile and stereoselective intramolecular Michael addition of C-12 O-carbamates to an alpha , beta -unsaturated ketone. The Michael reaction required base catalysis and the rate of addition was fastest in polar solvents such as 10% aqueous acetonitrile or dimethylformamide. Reaction of the key intermediate acyl imidazole 11a with primary amines produced in one operation the cyclic 11,12-carbamates. The stereochemistry of the product carbamates was determined by minimum energy calculations, two-dimensional NMR spectroscopic techniques, and super(13)C NMR correlation.