Biomimetic synthesis of (+/-)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction.
(+/-)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3',4',5'-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.
Node
Manabu
M
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto, Japan. node@mb.kyoto-phu.ac.jp
Kodama
Sumiaki
S
Hamashima
Yoshio
Y
Katoh
Takahiro
T
Nishide
Kiyoharu
K
Kajimoto
Tetsuya
T
D005702:Galantamine / Q000138:chemical synthesis*; D008958:Models, Molecular; D015394:Molecular Structure; D010277:Parasympathomimetics / Q000138:chemical synthesis*
D010277:Parasympathomimetics; D005702:Galantamine