The Chemistry of the Nargenicin Macrolides

The search for natural products possessing antibiotic activity against drug-resistant microorganisms continues to uncover a fascinating array of biologically active compounds. The recent discovery of a new structural class of macrolide antibiotics, the nargenicins, demonstrates the continuing role of natural products isolation as a catalyst for research in a multidisciplinary host of areas, including bioorganic, medicinal, and synthetic organic chemistry. This chapter reviews recent efforts to define the structure, activity and biological origin of the nargenicins, and examines progress toward the total synthesis of naturally occurring nargenicin macrolides. Considerable progress has been recorded toward the synthesis of naturally occurring nargenicin, and an efficient, reliable and preparadvely useful strategy for development of nargenicin carbon frameworks has emerged. Key issues in this area that remain to be explored include (1) effective, asymmetric entries to the oxa-bridged nargenicin octalin systems, (2) reliable procedures for control of macrocycle chirality, especially the C2 stereogenic center, (3) efficient strategies for addressing the synthesis of highly-oxygenated nargenicin congeners such as the B series of nargenicins and coloradocin.