Asymmetric Synthesis of Tetrabenazine and Dihydrotetrabenazine

Abstract

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.

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

“…Rishel et al completed the first asymmetric synthesis of (+)- 1 by the use of Sodeoka’s palladium-catalyzed asymmetric malonate addition as the key step [15]. High optical purity (ee >97%) and reasonable yields were achieved in this eight-step synthesis.…”

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

“…Scheme 7 shows the first asymmetric synthesis of (+)-TBZ [19]. The crucial chiral center in TBZ The racemic mixture of α-HTBZ can be also separated using a similar protocol, as shown in Scheme 6 [18].…”

“…In addition, the approval of TBZ has led to the further investigations on this classic molecule in terms of its stereoisomerism [16] and pharmacokinetics [17]. To overcome the stereoisomerism issue in particular, a variety of chiral separation [16,18] and asymmetric synthetic methods have been reported [19]. In addition to this problem, the rapid metabolism of TBZ is also a significant issue [17].…”

PET radioligands for the vesicular transporters for monoamines and acetylcholine

“…Syntheses of the two chirally resolved desmethyl precursors were originally carried out using selective O‐demethylation of racemic α‐DTBZ and tedious isolation of the desired mono‐demethylated product, followed by preparative chiral chromatographic separation, and isolation of the (+) and (−)‐α‐9‐ O ‐desmethylDTBZ isomers . In more recent years, there have been a number of new synthetic approaches to the synthesis of TBZ and DTBZ, which allow simpler preparations of this class of molecules …”

“…14 In more recent years, there have been a number of new synthetic approaches to the synthesis of TBZ and DTBZ, which allow simpler preparations of this class of molecules. [19][20][21] The (+)-a-[ 11 C]DTBZ ( Figure 1) has become the preferred in vivo positron emission tomography (PET) radioligand for studies of the VMAT2 in normal and diseased brain: the synthesis of the radioligand has now been reproduced by multiple research groups using solution chemistry, loop chemistry, and solid-phase-supported chemical synthesis techniques. The dynamic PET data obtained from the human PET studies can be readily applied to pharmacokinetic models, or utilized in graphical analyses, to yield estimates of binding potential for this radiopharmaceutical.…”