The first example of the stereoselective synthesis of 7 beta-carbamoyl-4,5alpha-epoxymorphinan via a novel and reactive gamma-lactone.
7beta-Carbamoyl-4,5alpha-epoxymorphinans 5 were stereoselectively synthesized from the 7alpha-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 gamma-lactone 7. These were the first examples of the stereoselective syntheses of 7beta-substituted 4,5alpha-epoxymorphinans. The mechanism of the reaction process was elucidated as follows: 1) epimerization of 7alpha-carboxylate 3, 2) intramolecular lactonization of 7beta-carboxylate 6, and 3) aminolysis of the resultant gamma-lactone 7. The aminolysis of the isolated reactive gamma-lactone 7 with allylamine and the alcoholysis with MeOH in the presence of NaBH(4) proceeded at room temperature. The gamma-lactone 7 can be a useful intermediate for the preparation of 7beta-substituted 4,5alpha-epoxymorphinans that would be potent selective delta opioid receptor ligands. The stereoselective syntheses of the 7alpha-carbamoyl-4,5alpha-epoxymorphinans 9 from 7alpha-carboxylate 3 via 7alpha-carboxylic acid were also successful.
Fujii
Hideaki
H
Pharmaceutical Research Laboratories, Toray Industries Inc., 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Hirano
Noriyuki
N
Uchiro
Hiromi
H
Kawamura
Kuniaki
K
Nagase
Hiroshi
H
D007783:Lactones / Q000138:chemical synthesis*; D009019:Morphinans / Q000138:chemical synthesis*; D013237:Stereoisomerism
D007783:Lactones; D009019:Morphinans