The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

[reaction: see text] Studies on the connection between the right and left segments of azadirachtin are described. The Ireland-Claisen rearrangement of Li-enolate of the modeled ester with dichlorodimethylsilane in toluene afforded the desired limonoid framework stereoselectively in good yield.

D-Desosamine is synthesized in 4 steps from methyl vinyl ketone and sodium nitrite. The key step in this chromatography-free synthesis is the coupling of (R)-4-nitro-2-butanol and glyoxal (trimeric form) mediated by cesium carbonate, which affords in crystalline form 3-nitro-3,4,6-trideoxy-α-D-glucose, a nitro sugar stereochemically homologous to D-desosamine. This strategy has enabled the syntheses of an array of analogous 3-nitro sugars. In each case the 3-nitro sugars are obtained in pure form by crystallization.

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