Preparation of Optically Active Succinic Acid Derivatives. I. Optical Resolution of 2-Benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic Acid.

Abstract

(+)-Monocalcium bis[(2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionate] dihydrate (KAD-1229, 1) is an optically active succinic acid calcium salt derivative with potent hypoglycemic effect. We investigated two optical resolution methods. 2-Benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid 6 was esterified with (S)-N-benzyl mandelamide and the resulting diastereomeric esters were separated by column chromatography on silica gel to give 7 and 8 in 39.1% and 45.3% yields, respectively. The diastereomer 7 was hydrolyzed to give the optically active acid (-)-6. The absolute configuration of (-)-6 was established as S by comparison with an authentic sample. The alternative method was resolution using an optically active amine. Treatment of a solution of the racemic acid 6 with 0.65 eq of (R)-1-(1-naphthyl)ethylamine in ethanol gave the salt in 23.2% yield with an optical purity of 96.8% ee.