Latent‐Functionality‐Based Synthesis of the Furanoside Motif of Hygromycin A

A latent functionality strategy is employed to construct the β-hydroxy ketone motif within the sugar fragment of hygromycin A through the 1,3-dipolar cycloaddition of furan. Facile epimerization at the C5 position enables access to both the natural congeners of hygromycin A and structurally modified derivatives for potential medicinal applications.

Hygromycin A, a once-forgotten antibiotic first isolated in 1953, is recently rediscovered as a novel inhibitor of Lyme disease caused by Borrelia burgdorferi. Given the increasing resistance of gut microbes to antibiotic treatments, there is an urgent need for new therapies with novel mechanisms of action. The molecular architecture of hygromycin A, characterized by its fragmented structure, makes it an appealing platform for derivatization. In this study, it develops a latent functionality strategy to introduce the β-hydroxy ketone motif into the sugar fragment via the 1,3-dipolar cycloaddition of furan. The facile epimerization at the C5 position enables a rapid access congeners of hygromycin A. Furthermore, glycosylation with phenol derivatives provides a versatile method for establishing the unique stereogenic center of the furanoside in this class of compounds.

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