Abstract
This chapter discusses the strategies that have led to an optimized and robust process to synthesize the novel ketolide antibiotic ABT-773. The macrolide class of antibiotics has been at the forefront of medical research for many decades in combating infections caused by gram-positive bacteria. The quest for third generation macrolide antibiotics, for example, the ketolides, was primarily fuelled by the clinical need for agents displaying a broader spectrum of activity, higher efficacy against resistant bacteria, and better tolerability. The stereoselective conversion of the 11, 12-dihydroxy functionality to the corresponding cyclic carbamate moiety would complete the assembly of all the required functionalities present in ABT-773. Because of the known higher reactivity of the 6-hydroxyl group as compared to the hydroxyl groups at C-11 and C-12 positions under existing alkylation protocols used in the preparation of clarithromycin, it would be logical that the alkylation of 6-OH group should precede the 11,12-cyclic carbamate formation. Formation of the cyclic carbamate may be carried out prior to or after the formation of the 3-keto functionality to complete the synthesis of ABT-773; although both of these options have been demonstrated in the laboratory, the former approach is preferred. The need for the presence of a base during the cyclization process and the observed enhancement of rate of cyclization in polar solvents suggested a charge development in transition state and that the nucleophilic species is likely the imidate form of carbamate.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call