Synthesis of Analogs of GABA .15. Preparation and Resolution of Some Potent Cyclopentene and Cyclopentane Derivatives

Abstract

A series of cyclopentene and cyclopentane analogues of GABA has been prepared utilizing a thermal cis -trans isomerization of the phthalimido β,γ -unsaturated acid (10) as the key step to obtain trans-4- aminocyclopent-2-ene-1-carboxylic acid (7). Resolution of some of the potent GABA analogues, in particular (+)-(4S)- and (-)-(4R)-4- aminocyclopent-1-ene-1-carboxylic acid (5), has been achieved by crystallization of isopropylideneribonolactone esters or pantolactone esters of the phthalimido -protected intermediates.

Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABAC receptors

“…20 The deduced conformation for GABA A binding comes from our previous study 20 and other studies on conformationally constrained GABA analogues. 19,28,29 a The concentration that activates 50% of maximum response. All data are the mean AE SEMs (n = 3-4 oocytes).…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Hydrolysis of the unsaturated lactam affords 4-aminocyclopent-2-enecarboxylic acid (AE)-cis-(519) [366], which undergoes isomerization to gave 4-aminocyclopent-1-ene-1-carboxylic acid (AE)-(520) on treatment with 2 M NaOH [367]. Thermal cis-trans isomerization of (AE)-cis-(519) yields (AE)-trans-4-aminocyclopent-2-ene-1-carboxylic acid (AE)-trans-(521) [368].…”

“…Resolution of (AE)-(521) was achieved by crystallization of isopropylideneribonolactone esters or pantolactone esters of the phthalimido-protected intermediates to afford ( þ )-(S)-(521) and (À)-(R)-(521) [368]. Reduction of 3-(hydroxyamino)cyclopentanecarboxylic acid or its ethyl ester has also been used in the preparation of (518).…”

GABA Analogues Derived from 4-Aminocyclopent-1-enecarboxylic Acid

“…Both cis and trans isomers of saturated cyclopentane derivatives [cis-3-aminocyclopentanecarboxylic acid (CACP) and trans-3-aminocyclopentanecarboxylic acid (TACP)] are potent agonists at GABA A receptors [4][5][6]. Furthermore, of the possible unsaturated cyclopentene GABA analogues, 4-aminocyclopent-1-enecarboxylic acid (4-ACP-1-CA) is the most potent, and the activity resides in the (S)-isomer [1,7].…”

“…2-azabicyclo[2.2.1]hept-5-en-3-one, was generated by the Diels-Alder addition of tosyl cyanide (1) and cyclopentadiene (2) followed by mild acid hydrolysis [4]. Treatment of the lactam 3 with methanol and thionyl chloride gave the methyl ester hydrochloride (4) in high yields (up to 90%).…”