Abstract
Clarithromycin and congeners are important antibacterial members of the erythromycin A 14-membered macrocyclic lactone family. The macrolide scaffold consists of a multifunctional core that carries both chemically reactive and non-reactive substituents and sites. Two main approaches are used in the preparation of the macrolides. In semisynthesis, the naturally occurring macrocycle serves as a substrate for structural modifications of peripheral substituents. This review is focused on substituents in non-activated positions. In the total synthesis approach, the macrolide antibiotics are constructed by a convergent assembly of building blocks from presynthesized substrates or substrates prepared by biogenetic engineering. The assembled block structures are linear chains that are cyclized by macrolactonization or by metal-promoted cross-coupling reactions to afford the 14-membered macrolactone. Pendant glycoside residues are introduced by stereoselective glycosylation with a donor complex. When available, a short summary of antibacterial MIC data is included in the presentations of the structural modifications discussed.
Highlights
Clarithromycin (B, Figure 1) and congeners are antibacterials from the erythromycin A14-membered lactone family
This review describes work on modifications of chemically inert carbon substituents and non-activated sites in the scaffold congeners of clarithromycin ketolides [4,5,6]
In telithromycin (C) and solithromycin (D), the 3-glycocyl function has been cleaved by hydrolysis and the resultant 3-hydroxy group oxidized to afford the 3-ketolide
Summary
Clarithromycin (B, Figure 1) and congeners are antibacterials from the erythromycin A. This review describes work on modifications of chemically inert carbon substituents and non-activated sites in the scaffold congeners of clarithromycin ketolides [4,5,6]. The semisynthetic drug, clarithromycin, is a 6-methyl ether of the parent 14-membered erythromycin A. Removal of the 3-(L)-desosamine sugar residue in erythromycin and oxidation of the resultant free 3-hydroxy group afford highly active 3-oxo antibacterials. In telithromycin (C) and solithromycin (D), the 3-glycocyl function has been cleaved by hydrolysis and the resultant 3-hydroxy group oxidized to afford the 3-ketolide.
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