On the synthesis of mono amides of 18-crown-6-tetracarboxylic acid

The synthesis of monoamides of (R,R,R,R)-18-crown-6-2,3,11,12-tetracarboxylic acid via reaction of primary and secondary amines with the crown ether bis-anhydride is explored. One equivalent of benzylamine gave a quantitative yield of a diamide, and the recovered crown ether suffered epimerization. The expected monoamide was prepared via initial partial hydrolysis of the bis-anhydride followed by benzylamine addition. The initial hydrolysis method fails for secondary amines, as nucleophilic attack is not competitive with epimerization. As a consequence, the stereochemical integrity of the starting material is lost and amide ester derivatives of this important framework crown ether are inaccessible by direct refunctionalization.