| Moenomycin A is the only known antibiotic to directly inhibit the transglycosylases that are essential for bacterial survival. Although substantial synthetic efforts have been directed toward moenomycin A over the last three decades, a total synthesis has not been reported. This thesis describes the synthesis of a protected pentasaccharide consisting of the A, B, C, D, E, and F units of moenomycin A. This pentasaccharide can be converted into moenomycin A by attachment of the lipid phosphoglycerate unit.; Synthesizing the challenging glycosidic linkages present in moenomycin A allowed for a stringent test of the sulfoxide glycosylation method. A newly discovered side reaction of sulfoxide glycosylations that led to substantial losses of the glycosyl acceptor, conversion of hydroxyls into benzenesulfinic esters, was observed. Methods to suppress this byproduct from forming were developed that enabled substantially higher glycosylation yields. Different methods to activate glycosyl sulfoxides were also evaluated in the synthesis of moenomycin, with the inverse addition protocol proving essential in obtaining the fully protected pentasaccharide in high overall yield. An effective method to construct beta-1,4-glycosidic linkages between two glucosamine derivatives, using the sulfoxide glycosylation method, is also described in this thesis.; The synthesis of the protected moenomycin A pentasaccharide, combined with the successful attachment of the lipid phosphoglycerate unit recently accomplished by our group, allowed for the first total synthesis of moenomycin A. The synthetic route allows for ready access to moenomycin derivatives ranging in complexity from monosaccharides to pentasaccharides. These derivatives can be used to learn more about moenomycin's mechanism of action, biosynthesis, and structural requirements for activity. |
