Synthesis and Antihypertensive Activity of 5-(2-Hydroxyphenyl)-1-(3-mercaptopropionyl)-2-pyrrolidinecarboxylic Acids

The (2S, 5R)-(+)- or (2R, 5S)-(-)-thiol (4a or 4b) was synthesized by catalytic hydrogenation of the corresponding (S)-(-)- or (R)-(+)-pyrrolinecarboxylic acid (8a or 8b) resolved with (R)-(-)-1, 2-diphenylethylamine, followed by acylation with 3-(benzoylthio) propionyl chloride and ammonolysis. The thiols were converted into the corresponding O, S-diacetates (16a and 16b), which were transformed into (2R, 5R)-(+)- and (2S, 5S)-(-)-thiols (18a and 18b) via their O, S-diacetates (17a and 17b) by epimerization and then ammonolysis. The stereochemistry of these thiols was elucidated on the basis of synthesis from tert-butoxycarbonyl-L-glutamic acid γ-benzylester (9) and proton nuclear magnetic resonance (1H-NMR) analysis. The thiols were tested for inhibitory activity against angiotensin-converting enzyme in vitro. (2S, 5R)-5-(2-Hydroxyphenyl)-1-(3-mercaptopropionyl)-2-pyrrolidinecarboxylic acid (4a) showed the most potent activity among them.