Synthesis of a transition state analogue for the hydrolysis of cocaine: Assistance to phosphonylation of a 3β-hydroxytropane by a neighbouring amide group

A simple synthesis of phenylphosphonate monoester analogues of the transition state for hydrolysis of the benzoyl ester group in cocaine is provided by the reaction of 2β-amido-3β-tropanols with phenylphosphonyl dichloride. Steric hindrance to phosphonylation of the hydroxyl is overcome because the neighbouring 2β-amido group participates in the reaction. The intramolecular assistance by the amide to formation of the phosphonate ester is influenced by the electronic environment of the amide group.