Synthesis of 14,15-dehydroerythromycin A ketolides: effects of the 13-substituent on erythromycin tautomerism.

A ketolide was prepared from 14,15-dehydroerythromycin A by two different routes. The first approach involving oxidation of the 3-OH of 3-descladinosyl-14,15-dehydroerythromycin A 2'-O-acetate gave unexpectedly high levels of 3,11-double oxidation. This may be due to greater formation of the 9,12-hemiketal in 14,15-dehydroerythromycin A and concomitant exposure of the 11-OH group for oxidation. NMR studies of 14,15-dehydroerythromycin A support this hypothesis, revealing a 9:1 ratio of 9-ketone to 9,12-hemiketal in CDCl3 and a 1:1 ratio in CD3OD as contrasted with the corresponding tautomer ratios of 30:1 in CDCl3, and 6: 1 in CD3OD with erythromycin A. Alteration of the 13-substituent on the erythronolide A ring from ethyl to vinyl thus favors formation of the 9,12-hemiketal. A second route to the ketolides was developed based on these findings, in which the 11-OH is eliminated prior to oxidation of the 3-OH.