Synthesis of 14-Membered Ring Macrolide Analogs

Date of Completion

January 2010


Chemistry, Organic|Health Sciences, Pharmacy




The increasing resistance to antibiotics is becoming a major threat to public health. An increasing number of multi-drug resistant pathogens threaten the clinical usefulness of many of the currently used antibacterial agents. There is a clinical need for new antibiotics that are active against resistant bacteria and also have a low potential to induce antibiotic resistance. To this end, macrolides and ketolides are of interest as an old and well-known family of oral antibiotics commonly used in the treatment of upper respiratory tract infections. There is an on-going search for semisynthetic macrolide derivatives with an improved antibacterial profile. ^ Taking advantage of ring-closing metathesis, we have developed a methodology that enabled us to convert naturally produced methyl (-)-nonactate into 14-membered ring macrocyclic compounds closely resembling the macrolactone portion of macrolide antibiotics. Our initial route had to be modified to overcome some significant synthetic obstacles. Further work is needed to find an efficient glycosidation strategy for incorporating a desosamine residue into the analog structure. New and synthetically useful molecules for macrolide analog synthesis were produced. Other variations of this strategy should be possible and could lead to a variety of unique chemical structures. ^