A Chiral Synthesis of Four Stereoisomers of 1, 3-Dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, an Inducer of Parkinson-like Syndrome

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 1; pp. 91 - 98
• Main Authors: TODA, Jun, MATSUMOTO, Shinobu, SAITOH, Toshiaki, SANO, Takehiro
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.01.2000; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 1, 3-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; chiral synthesis; Chromatography, High Pressure Liquid; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Isoquinolines - chemistry; Isoquinolines - toxicity; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Molecular Conformation; Organic chemistry; Parkinson Disease, Secondary - chemically induced; parkinsonism; Pharmacology & Pharmacy; Physical Sciences; Preparations and properties; Pummerer reaction; Science & Technology; Stereoisomerism; tetrahydroisoquinoline; Tetrahydroisoquinolines; INTRAMOLECULAR CYCLIZATION; 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline chiral synthesis; parkinsonism; Pummerer reaction; DISEASE; MOUSE; tetrahydroisoquinoline; 1-METHYL-1,2,3,4-TETRAHYDROISOQUINOLINE; BRAIN; 1-BENZYL-1,2,3,4-TETRAHYDROISOQUINOLINE; Parkinsonism; Stereoselectivity; Aminoalcohol; Asymmetric synthesis; Nitrogen heterocycle; Bicyclic compound; Aromatic compound; Chemical synthesis; Primary amine
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.48.91

Four stereoisomers of 1, 3-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, an inducer of Parkinson-like syndrome, were synthesized by applying a new method of 1, 2, 3, 4-tetrahydroisoquinoline (TIQ) synthesis utilizing the Pummerer reaction as a key step. The chiral centers at C-1 and C-3 were constructed by two routes starting from alaninol (3) and 1-phenylethylamine (4) as a chiral source. Enantiomerically pure 1, 3-dimethyl-TIQs (1R, 3S)-(1), (1S, 3R)-(ent-1), (1S, 3S)-(2), and (1R, 3R)-(ent-2) were prepared in a stereochemically unambiguous manner from 3 in 11 steps (route I) and from 4 in 6 steps (route II). The conformations of tetrahydroisoquinoline ring in 1-methyl, 3-methyl, and 1, 3-dimethyl-TIQs were discussed on the basis of their CD, 1H-NMR spectra, and steric energies.