The first example of the stereoselective synthesis of 7 β-carbamoyl-4,5 α-epoxymorphinan via a novel and reactive γ-lactone

Abstract

7 β-Carbamoyl-4,5 α-epoxymorphinans 5 were stereoselectively synthesized from the 7 α-carboxylate intermediate 3 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines under reflux conditions in mesitylene via a novel and reactive γ-lactone 7. These were the first examples of the stereoselective syntheses of 7 β-substituted 4,5 α-epoxymorphinans. The mechanism of the reaction process was elucidated as follows: 1) epimerization of 7 α-carboxylate 3, 2) intramolecular lactonization of 7 β-carboxylate 6, and 3) aminolysis of the resultant γ-lactone 7. The aminolysis of the isolated reactive γ-lactone 7 with allylamine and the alcoholysis with MeOH in the presence of NaBH 4 proceeded at room temperature. The γ-lactone 7 can be a useful intermediate for the preparation of 7 β-substituted 4,5 α-epoxymorphinans that would be potent selective δ opioid receptor ligands. The stereoselective syntheses of the 7 α-carbamoyl-4,5 α-epoxymorphinans 9 from 7 α-carboxylate 3 via 7 acarboxylic acid were also successful. © 2004 Pharmaceutical Society of Japan.