Preparation of exo-6-benzyl-exo-2-(m-hydroxyphenyl)-1-dimethylaminomethylbicyclo[2.2.2.]octane. A non-peptide mimic of enkephalins

Abstract

A model for the active conformation of methionine enkephalin was derived from computer modeling. From this model, a target was designed and synthesized using bicyclo[2.2.2]octane as a structural template. Thus, a key intermediate, exo-6-benzoyl-1-carboethoxybicyclo[2.2.2]-2-octene was prepared via a Diels–Alder reaction using ethyl dihydrobenzoate and phenylvinylketone. It was subsequently modified to exo-6-benzyl-1-dimethylaminobicyclo[2.2.2]-2-octene. This intermediate was hydroborated and oxidized to the ketone on which the second aromatic group was introduced using a Grignard reaction, eventually giving rise to the desired target, exo-6-benzyl-exo-2-(m-hydroxyphenyl)-1-dimethylaminobicyclo[2.2.2]octane. Biological testing demonstrated weak activity with this compound.