Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

Abstract

Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington's disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson's disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.

Keywords: Huntington’s disease; Parkinson’s disease; dopamine; tetrabenazine; vesicular monoamine transporter type 2.

Figure 1

The structures of dopamine, 5-hydroxytryptamine, reserpine, and tetrabenazine (TBZ).

Figure 2

The metabolism of TBZ and the structures of its major metabolites.

Figure 3

The structures of valbenazine and deutetrabenazine.

Figure 4

TBZ-based positron emission tomography (PET) imaging agents.

Scheme 1

The classical synthesis of TBZ.

Scheme 2

The oxidation–Mannich cyclization sequence used in the synthesis of TBZ. rt: Room temperature; TFA: Trifluoroacetic acid; TIPS: Triisopropylsilyl; bpy: 2,2’-bipyridine.

Scheme 3

Synthesis of TBZ using an aza-Prins-type cyclization reaction. THP: Tetrahydropyran; HMDS: Hexamethydisilazane; THF: Tetrahydrofuran; Ts: p-toluenesulfonyl; Tf: Trifluoromethanesulfonyl; DMF: N,N-dimethylformamide; DDQ: 2,3-dichloro 5,6-dicyano 1,4-benzoquinone; MS: Molecular sieves; NMO: N-methylmorpholine N-oxide.

Scheme 4

The chiral separation of racemic α-HTBZ using enzymatic resolution.

Scheme 5

The chiral resolution of racemic TBZ using (1S)-(+)1−0-camphorsulfonic acid.

Scheme 6

The chiral resolution of racemic α-HTBZ using a tartaric acid derivative.

Scheme 7

Asymmetric synthesis of (+)-TBZ and (+)-α-HTBZ using an asymmetric malonate alkylation reaction. Boc: t-butoxycarbonyl; ee: Enantiomeric excess.

Scheme 8

Asymmetric synthesis of (+)-TBZ and (+)-α-HTBZ using an aza-Claisen rearrangement reaction. TBS: t-butyldimethylsilyl; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; TPAP: Tetrapropylammonium perruthenate.

Scheme 9

Asymmetric synthesis of (+)-α-HTBZ using ring-closing metathesis. NMP: N-methylpyrrolidine; Fmoc: Fluorenylmethoxycarbonyl; dba: Dibenzylidineacetone; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOAt: 1-hydroxy-7-azabenzotriazole; Cy: Cyclohexyl; H–G 2nd cat.: Hoveyda–Grubbs second generation catalyst.

Scheme 10

Asymmetric synthesis of (–)-α-HTBZ using a chiral sulfonamide. Bn: Benzyl.

Scheme 11

Synthesis of ¹¹C-labelled-TBZ. TBAOH: Tetrabutylammonium hydroxide.

Scheme 12

Synthesis of 9-O-desmethyl TBZ.

Scheme 13

Synthesis of ¹⁸F-propyl-(α)-HTBZ. HMPA: Hexamethylphosphamide; Ms: Methanesulfonyl.

Scheme 14

Synthesis of ¹³¹I-9-iodovinyl-TBZ.

Scheme 15

Synthesis of deutetrabenazine. DIAD: Diisopropyl azodicarboxylate.

Scheme 16

Synthesis of valbenazine. DCC: Dicyclohexyl carbodiimide; DMAP: 4-dimethylamino pyridine.