Asymmetric Synthetic Strategies of (R)-(–)-Baclofen: An Antispastic Drug

Abstract

Baclofen is an antispastic drug used as a muscle relaxant in the treatment of the paroxysmal pain of trigeminal neuralgia, spasticity of the spinal cord and cerebral origin. Baclofen resides biological activity exclusively in its (R)-(–)-enantiomer. In this review, various asymmetric synthetic strategies for (R)-(–)-baclofen are described.1 Introduction2 Resolution Synthetic Approaches2.1 Chemical Resolution2.2 Biocatalytic Resolution3 Asymmetric Desymmetrization3.1 Catalytic Enantioselective Desymmetrization3.2 Enzymatic Desymmetrization4 Chiral Auxiliary Induced Asymmetric Synthesis4.1 Asymmetric Michael Addition4.2 Asymmetric Aldol Addition4.3 Asymmetric Nucleophilic Substitution5 Asymmetric Reduction5.1 Catalytic Asymmetric Hydrogenation5.2 Bioreduction6 Catalytic Asymmetric Conjugate Addition7 Conclusion

Classics in Chemical Neuroscience: Baclofen

“…Baclofen (4-amino-3-(4-chlorophenyl)­butanoic acid, CAS 1134-47-0) has one chiral center, a molecular weight of 213.66 g/mol, and exists as a white, odorless crystalline powder. , The molecule contains two hydrogen bond donors, three hydrogen bond acceptors, and four rotatable bonds. Baclofen has p K a ’s of 3.89 and 9.79, with a tPSA of 63.32 Å 2 .…”

“…Baclofen abides by Lipinski’s rules and has an overall bioavailability between 70 and 85% . It is slightly soluble in water (0.712 mg/mL) and ethanol, and completely insoluble in chloroform . Baclofen ( 3 ) is sold under the trade names Lioresal (oral), Gablofen (injectable), Kemstro (disenegrating formulation), Lioresal intrathecal, and Ozobax (oral solution)…”

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

“…For example, (R)-enantiomers of Baclofen (antispastic agent and muscle relaxant) and Phenibut (tranquilizer and anticonvulsant) are considerably more active than the corresponding (S)-enantiomers, while anticonvulsant activity of Pregabalin (anti-epilepsy drug) is primarily related to (S)-enantiomer [23]. Consequently, considerable efforts were devoted to developing asymmetric synthesis of β-substituted GABA derivatives, including chemical and biocatalytic resolution, asymmetric reduction, desymmetrization, aldol addition, and nucleophilic substitution [24][25][26]. For the past decade, the asymmetric Michael addition of carbon nucleophile to α,β-unsaturated compoundbearing nitro or carbonyl groups gained impressive progress, providing straightforward access to γ-nitrocarbonyl compounds as key chiral intermediates that can be converted Significantly, biological activity of β-substituted GABA derivatives depends on their absolute configuration.…”

Highly Enantioselective Iridium-Catalyzed Hydrogenation of 2-Aryl Allyl Phthalimides

“…The asymmetric synthesis of chiral compounds is, therefore, an essential field in organic chemistry. In particular, chiral β-aryl propanamines are extremely interesting candidates as precursors of pharmaceuticals and active molecules: for example, Lorcaserin, an anorectic drug that has been typically synthesized by chiral resolution; OTS514, a marketed inhibitor of a serine-threonine kinase that is often overexpressed and transactivated in several types of cancer; and LY-392098, a potent positive allosteric modulator of 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic acid (AMPA) receptor . Moreover, we can envision the synthesis of several drug intermediates such as 3-methylindolines in few steps from β-aryl propanamines (Figure ).…”