Synthesis of 14, 15-Dehydroerythromycin A Ketolides: Effects of the 13-Substituent on Erythromycin Tautomerism

Abstract

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 CDC1₃ and a 1: 1 ratio in CD₃OD as contrasted with the corresponding tautomer ratios of 30:1 in CDC1₃, and 6:1 in CD₃OD with erythromycin A. Alteration of the 13-substituent on the erymronolide 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 the3-OH.