Enantiospecific Synthesis of All Four Stereoisomers of Novel Bicyclic Arylacetamides as k ‐Opioid Agonists

Conformationally constrained bicyclic derivatives of the potent and selective K‐opioid receptor agonist 2‐(3,4‐dichlorophenyl)‐ N ‐methyl‐ N ‐[(1S)‐1‐phenyl‐2‐(1‐pyrrolidinyl)‐ethlyl] acetamide (3, ICI‐199, 441) were designed to explore the effect of the conformational restriction and stereochemistry of the pharmacophoric ethylenediamine incorporated into the pyrrolidine on the affinity and K‐selectivity. A facile enantiospecific synthetic route was established to afford all four stereoisomers starting from readily available amino adds through mild cyclization and amide formation.