Inhibitors of GABA Uptake. Syntheses and 1H NMR Spectroscopic Investigations of Guvacine, (3RS,4SR)-4-Hydroxypiperidine-3-carboxylic Acid, and Related Compounds.

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Abstract
The syntheses of (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (8a) and guvacine (1,2,5,6-tetrahydropyridine-3-carboxylic acid) hydrobromide (9a), both potent inhibitors of GABA uptake, were described. (3RS,4SR,5SR)- and (3RS,4SR,5RS)-4-hydroxy-5-methylpiperidine-3-carboxylic acids (8c) and (8d) and the guvacine analog, (RS)-5-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (10) and 2,5,6,7-tetrahydro-1H-azepine-3-carboxylic acid and (1R,5S)-(-)-2-nortropene-2-carboxylic acid hydrobromides (14) and (18) were synthesized. The compounds 8a,c,d, 9a, 10, and 14 were prepared via catalytic hydrogenation of cyclic .beta.-oxoesters and appropriate acid treatments of the intermediate .beta.-hydroxy esters. Demethylation of ecgonine (16) followed by acid catalyzed hydrolysis and elimination reactions gave 18. (RS)-Perhydroazepine-3-carboxylic acid and (1R,2R,5R)-(+)-nortropane-2-carboxylic acid hydrobromides (15) and (19) were obtained by catalytic hydrogenation of 14 and 18, respectively. The relative stereochemistry of 19 was established by 270 MHz 1H NMR spectroscopy. The relationship between structure and potency as inhibitors of GABA uptake in animals of 8a,c,d, 9a, 10, 14, 15, 18, and 19 was discussed.