Synthesis of (±)-Tetrabenazine by Visible Light Photoredox Catalysis

Abstract

(±)-Tetrabenazine was synthesized in six steps from commercially available compounds. The key cyclization substrate was assembled rapidly via Baylis-Hillman and aza-Michael reactions. Annulation of the final ring was achieved through visible light photocatalysis, wherein carbon-carbon bond formation was driven by the oxidation of a tertiary amine. Solvent played a critical role in the photoredox cyclization outcome–whereas methanol led to a mixed ketal, acetonitrile/water (10:1) gave direct cyclization to (±)-tetrabenazine and occurred more rapidly.

Oxidative Difluoromethylation of Tetrahydroisoquinolines Using TMSCF2SPh: Synthesis of Fluorinated Pyrrolo[2,1-a]isoquinolines and Benzo[a]quinolizidines

“…Having the optimized reaction conditions in hand (Table , entry 11), we next examined the scope of the reaction with a variety of substituted tetrahydroisoquinoline derivatives 2 and the results are summarized in Scheme . In general, different substituents at the nitrogen atom including N -aryl, N -benzyl, N -allyl and N -homoallyl tetrahydroisoquinolines were suitable substrates leading to their corresponding products 3b – 3r in moderate to good yields (51–89% yields). Under the reaction conditions, alkene geometry of N -homoallylated tetrahydroisoquinolines 2o – 2r ( E isomer) underwent isomerization to yield 3o – 3r each as an inseparable mixture of E : Z isomers in good yields, presumably as a result from acidic reaction conditions.…”

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

“…Treating 7 with enone 8 lead to a conjugate addition reaction, keto-enol tautomerization, and concomitant Mannich reaction to produce TBZ 1. A chair-like transition state was used to explain the 1,4-anti relationship observed in the final product [35]. After this first synthesis, trimethylammonium salt 9, a precursor of enone 8, was successfully utilized under similar reaction conditions [36].…”

“…It was also possible afterward to improve or modify this route for the synthesis of TBZ analogs by other pharmaceuticals, such as Cambridge Laboratories or Biovail [37]. The use of a Mannich reaction, in situ oxidation using visible-light photo-redox catalysis, and a simultaneous cyclization strategy toward the synthesis of TBZ was reported in 2015, as shown in Scheme 2 [35]. This synthetic route features the use of tetrahydroisoquinoline 10 and an environmentally friendly photo-oxidation sequence [38].…”

Visible light photoredox and Polonovski-Potier cyclizations for the synthesis of (±)-5-epi-cermizine C and (±)-epimyrtine

“…These findings were applied to a concise synthesis of (±)-tetrabenazine, whereby the final annulation was accomplished by a photoredox Mannich cyclization. 12 The substrate in that work, an N-alkyl tetrahydroisoquinoline, was an excellent oxidation substrate due to its weak benzylic C-H bond and an aromatic ring that could stabilize the N-alkyliminium ion through conjugation. Herein we report the use of photoredox catalysis for the oxidative cyclization of a more challenging substrate-an N-alkyl piperidine that is devoid of stabilizing features and compare these results with a two-step stoichiometric Polonovksi-Potier cyclization.…”