Asymmetric synthesis of tetrabenazine and dihydrotetrabenazine.
The enantioselective synthesis of (+)-tetrabenazine (TBZ) and (+)-dihydrotetrabenazine (DTBZ), agents of significant interest for therapeutic and molecular imaging applications, has been completed in 21% (TBZ) and 16% (DTBZ) overall yield and in >97% ee from the starting dihydroisoquinoline. The synthesis utilizes Sodeoka's palladium-catalyzed asymmetric malonate addition to set the initial stereocenter followed by a number of diastereoselective transformations to incorporate the remaining asymmetric centers.
Rishel
Michael J
MJ
GE Global Research, One Research Circle, Niskayuna, New York 12309, USA. rishel@research.ge.com
Amarasinghe
Kande K D
KK
Dinn
Sean R
SR
Johnson
Bruce F
BF
D002384:Catalysis; D010165:Palladium / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
C032811:dihydrotetrabenazine; D010165:Palladium; D013747:Tetrabenazine