β‐Carbolines from Japanese Sake and Soy Sauce: Synthesis and Biological Activity of Flazin and Yellow Substance YS (Perlolyrine)

Abstract

The P-carbolines flazin (1) and perlolyrine (2, substance YS) occuring in J apanese sake and soy sauce were synthesized starting with the methyl ester of L-tryptophan or tryptamine, respectively. The inhibition of the monoamine oxidases A and B by 1 and 2 were determined and compared with theinhibitory effects of harmine and harmaline. 0-Carboline aus japanischem Sake und aus Soya-Sauce: Synthese und biologische Aktivitat des Flazins und der gelben Substanz YS (Perlolyrh) ~i~ p-Carboline plazin (1) und Substanz ys = perlolyrinis (2), die in japanischem Sake und japanischer s~~~. s~~~~ vorkommen, wurden ausgehend von L-Tryptophanmethylester respektive Tryptamin synthetisiert. Die Hemmung der Monoaminoxidasen A und B durch 1 und 2 wurde im Vergleich mit Harmin und Harmalin gemessen.The highly fluorescent P-carbolines flazin and substance YS, isolated from Japanese soy sauce, were reportet to have structures 1 and 2 respectively'). Both compounds also occur in Japanese saks), and 2 seems furthermore to be identical with the alkaloid perlolyrine isolated from ryegrad). Perlolyrine (2) was synthesized from (+)-tryptophan and its structure confirmed by an X-ray analysis of its hydrobromideg). Flazin methylester (7) prepared by the Japanese investigators from flazin (1) with diazomethane') is structurally related to 3-(ethoxycarbonyl)-P-carboline (CEE) which strongly binds to benzodiazepine receptors4) and has for this reason aroused considerable interest. Perlolyrine (2), on the other hand, is structurally related to the Harmalu alkaloid harmine, a known inhibitor of monoamine oxidase As). The presence of 1 and 2 in food and their chemical relationship to well known psychomimetics provided incentive to prepare them in sufficient quantity for testing.The route chosen by us resembles in principle the reported synthesis of Z3), obtained from (+)-tryptophan by PictetSpengler reaction with 5-(acetoxymethyl)furfural, and followed by oxidation of the reaction products with chromic acid3), but varies in details.Direct condensation of L-tryptophan with commercially available 5-(hydroxymethy1)furfural 6, did not readily yield the desired tetrahydrocarbolines. However, success was achieved when the methyl or ethyl ester of L-tryptophan was reacted with 5-(acetoxymethy1)furaldehyde in refluxing benzene in the presence of a catalytic amountof p-toluene-sulfonic acid to yield Schiff base 3, which cyclized spontaneously to a 3 5 mixture of cis-and trans-tetrahydrocarbolines 4 and 5, respectively. The mixture could be separated by column chromatography and configuration of the two compounds was established on the basis of C-13 NMR data7! Aromatization of 4 and 5 with Pt/C catalyst in the presence of oxygen afforded the desired carboline 6, with a faster aromatization rate noted for trans isomer 5. Removal of the acetyl group in 6 with 0.5 % NH40H in methanol led to compound 7, identical with flazin methylester '). Hydrolysis of 6 in 0.1 N methanolic NaOH yielded a yellow, crystalline product, identical with flazin 1'). Attempts to ...

[2+2+2] Cycloadditions of Alkynylynamides – A Total Synthesis of Perlolyrine and the First Total Synthesis of “Isoperlolyrine”

“…Initial attempts to perform Sonogashira and Negishi couplings of the diynes with 5-bromofurfuryl alcohol or its protected derivatives (O-MOM or O-THP) failed or led to unstable products in poor yields. Much better results (up to 81 % yield) were obtained in Negishi coupling reactions of diynes 8a,b and 5-bromofuroic ester (9). This ester group will be reduced to the primary alcohol in a later step.…”

“…Starting with tryptophan or tryptamine, the classical Pictet-Spengler and Bischler-Napieralski condensations are the key steps of these approaches. [6,9] [a] Institute for Organic Chemistry, Johannes Gutenberg University Mainz, the β-and γ-carboline cores. The choice of the catalyst strongly affects the β/γ ratio.…”

Cellular Effects Of Tamari Soy Sauce-derived 1-[5-(Hydroxymethyl)furan-2-yl]-9H-pyrido[3,4-b]indole-3-carboxylic Acid (Flazin)

“…The aim of the present study was to refine 1-[5-(Hydroxy-methyl)furan-2-yl]-9H-pyrido [3,4-b] indole-3-carboxylic acid (Flazin) from the main body of collected soy sauce (Gessner et al, 1988) and to examine the cellular effects of this compound.…”

“…Flazin was first separated from sake lees as a crystal during the manufacture of synthetic sake (Gessner et al, 1988) and has been found to exhibit strong fluorescence (Li et al, 2011). Flazin was also discovered as a cluster of dark green microcrystals in rice vinegar during a research study on soy sauce (Gessner et al, 1988).…”

“…Flazin was also discovered as a cluster of dark green microcrystals in rice vinegar during a research study on soy sauce (Gessner et al, 1988). The structure of Flazin was determined by Nakatsuka et al (1986).…”