Synthesis and resolution of 2-methyl analogues of GABA Rujee K. Duke, a,b, * Mary Chebib, a David E. Hibbs, c Kenneth N. Mewett b and Graham A. R. Johnston b a Faculty of Pharmacy, University of Sydney, Sydney NSW 2006, Australia b The Adrian Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, University of Sydney, Sydney NSW 2006, Australia c School of Chemistry, University of Sydney, Sydney NSW 2006, Australia Received 19 March 2004; accepted 2 April 2004 Available online 10 May 2004 Abstract—E-4-Amino-2-methylbut-2-enoic acid, ()-4-amino-2-methylbutanoic acid, (þ)-(S)- and ()-(R)-4-amino-2-methylbu- tanoic acid, which are analogues of the inhibitory neurotransmitter GABA (c-aminobutyric acid, 4-aminobutanoic acid), were synthesised from ethyl 2-methyl-4-phthalimidobut-2-enoate, ethyl 2-methyl-4-phthalimidobutanoate, (þ)-[(2R-(3,3-dimethylbutyro- 1,4-lactonyl)]-(2S)-methyl-4-phthalimidobutanoate and ()-[(2R-(3,3-dimethylbutyro-1,4-lactonyl)]-(2R)-methyl-4-phthalimido- butanoate, respectively. The assignment of the absolute configuration of (þ)-(S)- and ()-(R)-4-amino-2-methylbutanoic acid was based on the X-ray crystallographic structure of the (þ)-(R,S)-diastereoisomer, and direct comparison of specific rotations with the published data for ()-(R)-4-amino-2-methylbutanoic acid. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction 4-Aminobutanoic acid (c-aminobutyric acid, GABA) 1 (Fig. 1) is the major inhibitory neurotransmitter in the brain. GABA mediates its action via GABA receptors, ionotropic GABA A and GABA C receptors and G-pro- tein coupled GABA B receptors. 1 GABA A and GABA C receptors are neurotransmitter gated chloride channel receptors. GABA receptor channels open in response to the binding of GABA. The opening of chloride channels allows chloride ions to follow their electrochemical gradient and enter the neuronal cell. Influx of chloride ions is considered inhibitory as it lowers the membrane potential and restores stability to excited neuronal membranes. The GABA recognition site at GABA C receptors is proposed to be narrow 2 and a substituent on the GABA backbone especially on C2 can have a strong effect on the receptor activity. E-4-Amino-2-methylbut-2-enoic acid (trans-2-methylcrotonic acid, 2-MeTACA) 3 (Fig. 1) is a moderately potent antagonist at GABA C recep- tors (K B 31 lM) while the parent compound E-4-amino- but-2-enoic acid [trans-aminocrotonic acid (TACA)] 2 (Fig. 1) is a potent agonist (K D 2.4 lM) exhibiting a maximal response of 93% of GABA-activated cur- rent, which is not significantly different from a full * Corresponding author. Tel.: +61-2-9351-6204; fax: +61-2-9351-3868; e-mail: rujeek@pharmacol.usyd.edu.au N H 2 OH O N H 2 OH O N H 2 OH O N H 2 OH O N H 2 OH O 2 3 N H 2 OH O S N H 2 OH O R N H 2 OH O RS N H 2 OH O R S (±)-CAMP 5 GABA 1 (±)-2-MeGABA 4 Agonist Partial agonist Agonist (-)-CAMP 5b (-)-(2R)-MeGABA 2-MeTACA 3 4b Antagonist Antagonist (+)-CAMP 5a (+)-(2S)-MeGABA 4a TACA 2 Agonist Agonist Figure 1. Structures of GABA C receptor agonists and antagonists. 0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2004.04.002 Tetrahedron: Asymmetry 15 (2004) 1745–1751 Tetrahedron: Asymmetry