A concise total synthesis of (+)-tetrabenazine and (+)-α-dihydrotetrabenazine.
Highly concise asymmetric total syntheses of (+)-tetrabenazine (1), a drug for the treatment of chorea associated with Huntington's disease, and of (+)-α-dihydrotetrabenazine (2), an active metabolite of 1, have been accomplished. Our synthetic route features a trans-selective enol etherification, followed by an unprecedented cation-dependent aza-Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)-2 and eight steps (22 % overall yield) for (+)-1.
Paek
Seung-Mann
SM
College of Pharmacy, Seoul National University, Seoul 151-742 (Korea), Fax: (+82) 2-888-0649.
Kim
Nam-Jung
NJ
Shin
Dongyun
D
Jung
Jae-Kyung
JK
Jung
Jong-Wha
JW
Chang
Dong-Jo
DJ
Moon
Hyunyoung
H
Suh
Young-Ger
YG
D002771:Cholera / Q000188:drug therapy; D006816:Huntington Disease / Q000188:drug therapy; D015394:Molecular Structure; D013237:Stereoisomerism; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C032811:dihydrotetrabenazine; D013747:Tetrabenazine
Claisen rearrangement; bentazines; rearrangement; total synthesis