Total synthesis of moenomycin A; exploring different reactive intermediates during sulfoxide glycosylation.

摘要

The bacterial cell wall is essential to the bacterial cell's survival. Although bacterial transglycosylases are a class of essential enzymes involved in cell wall biosynthesis, they have been poorly understood, partially due to difficulties in establishing biochemical assays. Understanding the mechanism of transglycosylases is important both to gain fundamental knowledge about cell wall biosynthesis and to explore their use as antibacterial drug targets. We envision that moenomycin, the only known inhibitor that directly binds to bacterial transglycosylase, might provide a unique tool to study these enzymes. However, due to its structural complexity and unclear mode of action, the ability to manipulate moenomycin is limited. In order to do so, a practical total synthesis of moenomycin is required. Numerous reports of synthetic attempts towards moenomycin A have been published over the past twenty years, but a total synthesis has not yet been accomplished, because this molecule presents a set of synthetic challenges. Herein, we reported the first total synthesis of moenomycin A, where all glycosidic linkages have been constructed using sulfoxide glycosylation.; More importantly, the synthesis of moenomycin A has provided us with a good opportunity to expand the repertoire of the sulfoxide method in the construction of some synthetically challenging glycosidic linkages and to better understand the mechanism of the sulfoxide glycosylation. We have discovered here that it is possible to utilize different reactive intermediates during the sulfoxide glycosylation, by changing the reaction protocol. This finding might have broader implications for other chemical glycosylation reactions.; In addition, we reported herein a chemical tool to profile bacterial transglycosylases---SMAP (small molecule affinity pulldown). A moenomycin-based probe was developed and successfully used to fish out different transglycosylases and their putative binding partners from different bacterial strains. This assay may open the door to understanding roles of transglycosylases during the cell cycle and the mechanism by which moenomycin inhibits transglycosylases.