Development of a Stereoselective Practical Synthetic Route to Indolmycin, a Candidate Anti-H. pylori Agent.

Abstract

Indolmycin (1), isolated from an African strain of Streptomyces albus, 1) exhibits antibacterial activity against Staphylococci.2) Recently, our screening group found that 1 also has potent antibacterial activity against Helicobacter pylori (H. pylori) and it is a promising anti-H. pylori agent.3)Although syntheses of 1, including its racemate, have been reported by several groups, 4) none of them is satisfactory for large scale synthesis because of low diastereoselectivity or involving too many chemical processes. Therefore, it was necessary to develop a stereoselective practical synthetic route to 1 for further study. In this paper, we wish to report a convenient and practical stereoselective synthesis of 1 from epoxy ester 3 as a starting material, through hydroxy ester 2 (Chart 1), and we show its application to the preparation of metabolites. ChemistryPreparation of an Intermediate Hydroxy Ester (؎)-2 Initially we started to study the diastereoselective synthesis of (Ϯ)-1 from (Ϯ)-3 which was easily prepared from ethyl crotonate by oxidation with m-chloroperbenzoic acid. We investigated the condensation of indolyl magnesium halide with (Ϯ)-3 although the coupling reaction of (Ϯ)-3 with indole in the presence of Lewis acid was reported.4e) Indole was treated with methyl magnesium bromide in ethyl ether to form indolyl magnesium bromide and the complex was isolated. Addition of (Ϯ)-3 to the reaction mixture gave the desired hydroxy ester (Ϯ)-2 in 48% yield after purification with silica gel column chromatography. The moderate yield was due to poor solubility of indolyl magnesium bromide in ethyl ether. It was reported that addition of dichloromethane to indolyl magnesium halide in ethyl ether brought the complex into a clear solution.5) Addition of (Ϯ)-3 to a solution of indolyl magnesium bromide in ethyl ether and dichloromethane gave (Ϯ)-2 in a better yield of 65%. By increasing the amount of methyl magnesium bromide (2.2 eq to 3) the yield was improved to 79% (Chart 2). Although the yield was satisfactory, it was necessary to purify the crude product by silica gel column chromatography to remove unreacted indole and by-products. As it was found that the hydroxy acid (Ϯ)-4 was easily purified by extraction and recrystallization, crude (Ϯ)-2 was hydrolyzed to (Ϯ)-4 and after purification, esterification of (Ϯ)-4 gave pure (Ϯ)-2 (Chart 2). Thus we accomplished the preparation of the racemic hydroxy ester (Ϯ)-2. Formation of the Oxazolone Ring Although Schach von Wittenau and Els 4e) and Preobrazhenskaya et al. 4a) reported that (Ϯ)-1 was prepared through formation of an oxazolone ring with N,NЈ-dimethylguanidine from the hydroxy ester (Ϯ)-2, the yields were very low, partly because the epimerization at C5 position of the oxazolone ring occurred in the alkaline medium. After intensive examination of the reaction, we found that epimerization was suppressed in tertbutanol below room temperature but the reaction was very slow (data was not shown). Therefore, we gave up the preparation of (Ϯ)-1 from the hydroxy es...

A Novel Tryptophanyl-tRNA Synthetase Gene Confers High-Level Resistance to Indolmycin

“…H and 13 C nuclear magnetic resonance spectra, as well as mass spectra, of the synthetic material were identical to those reported for authentic indolmycin (11). All amounts of (Ϯ)-synthetic indolmycin described herein are corrected to reflect only the active enantiomer.…”

Regulation of an Auxiliary, Antibiotic-Resistant Tryptophanyl-tRNA Synthetase Gene via Ribosome-Mediated Transcriptional Attenuation

“…Apramycin and hygromycin were used at 50 g/ml for selecting S. coelicolor. Indolmycin was chemically synthesized by the authors as described by Kamiyama et al (14) and used at 10 g/ml.…”

Glucuronidated Flavonoids in Neurological Protection: Structural Analysis and Approaches for Chemical and Biological Synthesis

“…For synthesis of quercetin glucuronide by this approach, 4′,7-dibenzylquercetin 15 102 was treated with methyl 2,3,4-tri- O -acetyl-1-bromo-α-D-glucuronate 5 /silver oxide (Ag2O) at 0°C to give a 52% yield of glucuronidated product; the final deprotection using Na 2 CO 3 in aqueous MeOH was more efficient 103,104 . The overall yield was considerably increased by reaction below room temperature 104 .…”