Synthesis of norbornane bisether antibiotics via silver-mediated alkylation

Abstract

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol <b>6</b>-was not successful using Williamson methodology but has been accomplished using Ag₂O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (<b>16d, 16g</b> and <b>16h</b>) exhibited antibiotic activity. For example, compound <b>16d</b> was active against a broad range of bacteria including <i>Pseudomonas aeruginosa</i> (MIC = 8 µg/mL), <i>Escherichia coli</i> (MIC = 8 µg/mL) and methicillin-resistant <i>Staphylococcus aureus</i> (MIC = 8 µg/mL).