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

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 11; pp. 1532 - 1537
• Main Authors: AKASAKA, Kozo, KOMATSU, Yuki, TAGAMI, Katsuya, SHIMIZU, Toshikazu, SHIMOMURA, Naoyuki, NAKA, Hiroshi, HAYASHI, Kenji, NEGI, Shigeto
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1999; Pharmaceutical Soc Japan; Maruzen
• Subjects: atrial natriuretic peptide; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; diastereomer differentiative reduction; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Life Sciences & Biomedicine; Organic chemistry; Pharmacology & Pharmacy; Physical Sciences; Preparations and properties; Science & Technology; stereoselective [5.7] ring formation; stereoselective [5.7] ring formation; atrial natriuretic peptide; PIPECOLIC ACIDS; diastereomer differentiative reduction; Intramolecular reaction; Sulfur nitrogen heterocycle; Condensation reaction; Peptidomimetic compound; Lactam; Atrial natriuretic peptide; Diastereoselectivity; Sulfur containing aminoacid; Stereoselectivity; Cyclization; Asymmetric reaction; Bicyclic compound; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.1532

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.