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Enantioselective Total Synthesis of Fortimicin B
Author(s) -
Lu Yang,
You XinYu,
Zhang Qianwei,
Lu QiTao,
Hou JunLi,
Cai Quan
Publication year - 2025
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202424235
Subject(s) - enantioselective synthesis , chemistry , stereochemistry , total synthesis , aminoglycoside , glycosidic bond , combinatorial chemistry , glycosylation , adduct , catalysis , antibiotics , organic chemistry , biochemistry , enzyme
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.