title: Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent.
abstract: A stereoselective practical synthetic route to indolmycin is described. The route is composed of the regioselective coupling of indolyl magnesium halide with a trans-epoxy ester, diastereoselective oxazolone ring formation with guanidine and amine exchange reaction with methylamine. In the coupling step, use of dichloromethane as co-solvent and conversion of the resulting hydroxy ester to the hydroxy acid for purification, make this process efficient and practical. The oxazolone ring is formed in good yield without epimerization at the C5 position by treatment with guanidine and potassium tert-butoxide in tert-butanol at room temperature. In the final step, the amino group is efficiently converted to the methylamino group in aqueous methylamine solution at 5 degrees C. After examination of the route with racemates, indolmycin was synthesized stereoselectively in 22% total yield from optically active trans-epoxy ester. This route was applied to the preparation of the metabolites of indolmycin.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Takeda Chemical Industries Ltd., Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hasuoka
authors.forename: Y
authors.initials: Y
authors.lastname: Nakayama
authors.forename: M
authors.initials: M
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: K
authors.initials: K
authors.lastname: Kamiyama
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001711:Biotransformation; D016480:Helicobacter pylori / Q000187:drug effects*; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D007211:Indoles; C001447:indolmycin