Enantioselective Total Synthesis of Fortimicin B

Abstract

Fortimicins, featuring a pseudodisaccharide scaffold, are an unusual class of aminoglycosides (AGs) with potent efficacy against several aminoglycoside-resistant bacterial strains. Notably, these molecules also exhibit lower inherent ototoxicity and nephrotoxicity than common aminoglycosides. Consequently, fortimicins are a promising type of protoypical molecules for the development of the next generation of aminoglycoside antibiotics. Here, we report the asymmetric total synthesis of fortimicin B in 12 steps (longest linear sequence, LLS) from readily available starting materials. An enantioselective Cu(II)-catalyzed inverse-electron-demand Diels–Alder (IEDDA) reaction of 2-pyrones and N-substituted 2-oxazolones was developed for the efficient synthesis of the fortamine fragment, which previously required a lengthy multistep synthesis owing to its complex stereochemistry. The 6-epi-purpurosamine B fragment was efficiently synthesized through a Cr(II)/Co(I)-mediated C─C bond coupling between aldehydes and alkyl halides. Within these two fragments, the stereoselective construction of the α-glycosidic bond of fortimicin B was realized via the gold(I)-catalyzed glycosylation. Overall, this study provides an efficient synthetic platform for future investigations into the structure–activity relationships of fortimicins.