Enantioselective Synthesis of Antispasmodic Drug (R)-Tiagabine
Enantioselective Synthesis of (R)-Tiagabine via Asymmetric Hydrogen Atom Transfer Protocol: L. Li, W. Chen, Z. Xu, J. Jiang, Y.-Q. Zhang
Synthesis 2023, DOI: 10.1055/a-2039-6180
Tiagabine is a selective antispasmodic drug marketed for the treatment of epilepsy. Structurally analogue to nipecotic acid, a the potent γ-aminobutyric acid (GABA) uptake inhibitor, it features a lipophilic bis-thiophenyl linker on the nitrogen atom, which allows for the requisite blood-brain barrier transport. The stereochemistry of the molecule is important, as the (R)-enantiomer is four times more potent than the (S)-enantiomer. To date only a limited number of stereocontrolled approaches to the title compound have been described. A novel stereoselective approach to (R)-tiagabine was recently reported by the group of Professor Yong-Qiang Zhang from Shandong University (P. R. of China).
Professor Zhang said: “We have demonstrated a novel synthetic approach to an antispasmodic drug tiagabine, utilizing a (salen)titanium-catalyzed asymmetric hydrogen-atom-transfer reaction developed by our group to construct its essential chiral tertiary carbon center. This strategy provides a scenario for the facile synthesis of the analogues and derivatives of tiagabine for further biological research.”