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 6—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 (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).

Norbornane-based cationic antimicrobial peptidomimetics targeting the bacterial membrane

“…The attachment of two guanidinium groups to the norbornane scaffold, using freshly prepared 2-[2,3-Bis( tert -butoxycarbonyl)guanidino]ethylamine ( 22 ),[34] was carried out over three steps. [24] Briefly, hydrolysis of the methyl esters gave dicarboxylic acid 19 in 88% yield. Standard EDCI/HOBt coupling conditions were employed to attach two units of 22 to the norbornane scaffold.…”

“…The rigid norbornane scaffold has previously been used to prepare preorganised anion hosts[21, 22] and in turn facially amphiphilic cationic peptidomimetics,[23–25] including bisethers (such as 1 , Figure 1)[24] and norbornane acetals (such as 2 ),[23] with both classes active against Gram-positive and Gram-negative bacterial strains. The acetal family were the more potent with structure-activity relationship (SAR) studies indicating that a dicationic charge and a long hydrophobic component were essential for activity.…”

Palladium‐Catalyzed Three‐Component Reactions for the Synthesis of Norbornane‐Fused Indanes

“…When 2-bromotoluene was used, the reaction did not occur and 2-bromotoluene almost remained intact. However, 5 a was obtained in 70% yield when 20 mol% of P(o-tol) 3 was added as a ligand. Subsequently, we examined the performance of iodobenzenes by using this new protocol ( (5 g and 5 h).…”

“…[2] The incorporation of a norbornane unit into organic molecules is of great significance in pharmaceutical chemistry as the norbornane scaffold encompasses unique three-dimensional shape and assorted pharmacokinetic properties. [3] Furthermore, in the field of supramolecular chemistry, polynorbornanes have been employed as ligands for the construction of metal-organic cages and as scaffolds for anion recognition. [4] Consequently, the construction of organic molecules containing norbornane units has attracted much attention from organic chemists.…”

Norbornene chaotropic salts as low molecular mass ionic organogelators (LMIOGs)

“… 13 , 17 , 18 Recently we have developed various examples of LMOGs from simple organic ligands that can, through self-association, or via coordination to either d- or f-metal ions, give rise to functional self-assembled gels. 19 – 25 In parallel, our ongoing interest in applications of functionalised norbornanes and related norbornylogous systems, 26 – 33 led us to synthesise simple norbornanes modified with amino-acids and here we report the development of such functionalised norbornenes as new low molecular mass ionic organogelators (LMIOGs) ( M W < 350 Da).…”