Synthesis of a New Dual Metalloprotease Inhibitor. II. Stereoselective Synthesis of Peptidomimetic [5.7]-Bicyclic Compounds

An efficient synthetic process for the key intermediate of a new peptidomimetic dual metalloprotease inhibitor, ER-40133, was developed. (5R)-Methyl-6-oxopipecolic acid ester (3a), prepared from L-α-aminoadipic acid, was chemoselectively reduced to the protected (5R)-methyl-6-hydroxypipecolic acid ester (4a), followed by treatment with L-cysteine methyl ester to give the linear key intermediate (5a) with the desired configuration. After deprotection of the ester moiety of 5a, the newly generated carboxylic acid group was intramolecularly condensed with the amino group at the thiazolidine ring using ethyl chloroformate in the presence of base to provide [5.7]-bicyclic compound (7a) with the desired configuration in excellent yield. Lastly, the methyl ester of 7a was hydrolyzed under alkaline conditions to afford 8a, a key intermediate for ER-40133.