Regioselective synthesis of N-functionalized 12-membered azapyridinomacrocycles bearing trialkylcarboxylic acid side chains

Selective protection of primary amine moieties of diethylenetriamine by 2-nitrophenylsulfonyl chloride followed by alkylation of the central N atom generates functionalized disulfonamide building blocks. When reacted with 2,6-bis(bromomethyl)pyridine following the Richman–Atkins methodology, such compounds yield the corresponding pyridine-containing azamacrocycles. Smooth removal of the N-sulfonyl groups provides versatile azamacrocyclic intermediates with transannular secondary amine functions. Subsequent N-alkylation regioselectively leads to tri N-functionalized 12-membered azapyridinomacrocycles bearing a sequence of N-acetate and N-propionate side chains.