Enantioselective Total Synthesis of Fortimicin B

This is the authors' abstract. We don't add key points for this paper.

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.