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DL- beta-3-oxindolylalanine (DL-hydroxytryptophan). 1. Synthesis

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... We were surprised to find very few reports of the apparently simple 1-benzyltryptophan (1) in the literature. Only six literature references were found in a Scifinder structurebased search, [13][14][15][16][17][18] and none of these references report the appended 1-benzyl group being used as a functional element. The obvious routes for the synthesis of 1 start with simple tryptophan analogs and involve deprotonation and alkylation of the side chain nitrogen atom. ...
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Proteins that recognize and bind quaternary ammonium ions depend on ''aromatic-cage'' structural motifs that use multiple aromatic residues to engage the side chain's ammonium cation. We introduce herein the use of 1-benzyltryp-tophan (Trp(Bn)) residues as synthetic, unnatural partial analogues of natural aromatic cages. We demonstrate the modular incorporation of these building blocks into simple dipeptide hosts and show that they are capable of binding quaternary ammonium ions in buffered water and in chloroform. Résumé : Les protéines qui reconnaissent et qui se lient à des ions ammonium quaternaires dépendent sur des motifs structuraux « cage aromatique » qui font appel à de multiples résidus aromatiques pour s'engager avec le cation ammo-nium de la chane latérale. Dans ce travail, on introduit l'utilisation des résidus 1-benzyltryptophane (Trp(Bn)) comme ana-logues partiels de synthèse, non naturels, des cages aromatiques naturelles. On démontre que l'incorporation modulaire des ces blocs dans des hôtes dipeptidiques et on montre qu'ils sont capables de se lier à des ions ammonium quaternaires dans l'eau tamponnée et dans le chloroforme. Mots-clés : reconnaissance moléculaire, tryptophane, peptides, interaction cation–p, effet hydrophobe.
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This chapter reviews developments in the field of isatin from 1944 to late 1974. The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide from an aniline, chloral hydrate, and hydroxylamine. The isonitrosoacetanilide is converted into the isatin on treatment with sulfuric acid, or less frequently polyphosphoric. The Sandmeyer method has been used with di- and trisubstituted aniline to prepare di- and tri-substituted isatins. Isatin sodium or potassium salts react with dimethyl and dieth sulfate, a variety of alkyl halides, acyl halides, and anhydrides to give N-alkyl and N-acylisatins. N-substitutcd isatins have also been prepared by reactions of some of the compounds that were described earlier. A number of reactions that do not reasonably fit in other categories are included in this chapter. A number of complexes of isatin and metal salts have been reported. Extensive studies have been reported on infrared vibrational frequency correlations of isatin and a variety of substituted isatin. A number of studies of the ultraviolet absorption spectra of isatins have appeared. The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. A wide variety of substituted isatins has reacted with hydroxylamine to give isatin-3-oximes. The cyclizations of certain 2-substituted isatin derivatives were studied so as to compare them with the above cyclizations. The chapter closes with a discussion on polymers.
The enzymes which catalyze reactions of molecular oxygen occur in three principle classes: (i) oxygen transferases, (ii) mixed function oxidases, and (iii) electron transferases. The first class catalyzes the transfer of a molecule of molecular oxygen to substrate. The second class catalyzes the transfer of one atom of the oxygen to substrate; the other atom undergoes two-equivalent reduction. The third class catalyses the reduction of molecular oxygen to hydrogen peroxide or to water.
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The chapter discusses the metabolism of phenylalanine, tyrosine, and tryptophan. Phenylalanine acid tryptophan is “essential” amino acids for higher organisms— that is, they cannot be synthesized by the organism and must be supplied in the diet. Tyrosine, formed from phenylalanine acid is not essential if the phenylalanine intake is adequate. The chapter presents biosynthesis, which is confined to lower organisms (bacteria, fungi, plants, etc.). Shikimic acid is a common precursor of the aromatic amino acids and of the bacterial growth factors, p-amino- and p-hydroxybenzoic acids. Phenylalanine and tyrosine are metabolized in higher organisms by two routes, which are quantitatively less important but physiologically of the highest importance. The first leads to the adrenal hormones adrenaline (epinephrine) and nonadrenaline (norepinephrine); this pathway also leads to melanin. The second leads to the thyroid hormones thyroxine and triiodothyronine, the synthesis and breakdown of which are also discussed. Tryptophan is metabolized in a wide range of organisms by a pathway involving: an unknown intermediate, formylkynurenine, kynurenine, hydroxykynurenine (or its phosphate), hydroxyanthranilic acid (or its phosphate), two unknown intermediates, and nicotinic acid. The relation of other vitamins to the pathway, side reactions giving such substances as anthranilic acid, kynurenic acid, and xanthurenic acid and the further degradation of nicotinic acid and its relation to the pyridine nueleotides are also considered. Tryptophan also gives rise to the important plant hormone, indoleacetic acid, and micro-organisms and especially plants metabolize the aromatic amino acids to a wide range of natural products, for example, certain antibiotics, alkaloids, flavonoids, and possibly lignin.
The chemistry of tryptophan (1) has probably been the object of more intense investigation than that of any other amino acids. This is undoubtedly due to the particular reactivity of the indole nucleus and to the extensive chemistry developed over the years regarding this important and ubiquitous functionality. Only the sulfur amino acids have received comparable attention from chemists and biochemists.
1.1.|A new group of enzymes was isolated from wheat germ and rat liver which oxidized the pyrrole ring of indoles affording o-formamidophenacyl derivatives. They behaved as mixed-function oxidases and were named pyrrolooxygenases. Tryptophan, ethyl N-acetyltryptophan, skatole, 3-indoleacetic acid, 3-indolepropionic acid and indole were substrates of the pyrrolooxygenases. The enzymatic oxidations were catalyzed by at least two enzymes within the group; one acting on tryptophan and its derivatives, and the other one acting on skatole and the other indoles.2.2.|The pyrrolooxygenases had an absolute requirement for oxygen and an exogenous reducing agent. The reducing agents were illuminated chloroplasts for the plant enzymes, and NADPH and a microsomal transport system for the mammalian enzymes. Both could be replaced by sodium dithionite.3.3.|Chelating agents, such as α,α′-dipyridyl and EDTA inhibited the enzymatic activity, while sodium cyanide had no effect. The enzymes were also inactivated by dithiothreitol and mercaptoethanol.4.4.|A natural heat-labile macromolecular inhibitor of the pyrrolooxygenases was present in the crude extracts and was separated during the successive purification steps.5.5.|Formamidase (EC 3.5.1.9) activity was present in the extracts together with the pyrrolooxygenases and transformed the o-formamidophenacyl derivatives into the corresponding o-amino derivatives. During the purification steps the formylase activity was partly removed.
Article
Die Oxydation von Indol-Derivaten einschlielich Tryptophan durch molekularen Sauerstoff, Autoxydation, Persuren und Enzyme fhrt primr zu -Hydroperoxy-und -Hydroxy--indolen. Solche Hydroxyindolenine zeigen folgende charakteristische Reaktionen:1 In saurem Medium gehen sieintermolekulare oder, falls geeignete Substituenten (zum Beispiel die Alanin-Seitenkette in Tryptophan) vorhanden sind,intra-molekulare Kondensation ein zu Verbindungen vom Eserolin-Typus. 2 Sie addieren unter anderm Wasser (a), Essigsure (b), Essigsureanhydrid (c), Persuren (d, X=Ac, Bz usw.), Wasserstoffsuperoxyd (d, X=H) zu Produkten, die formal hydratisierten Ketonen (a), deren Mono- (b) und Ortho-Azetaten (c) sowie Ketonhydroperoxyden (d) entsprechen. 3 Die oxydative Ringspaltung, die ber das Zwischenprodukt (d) erfolgt, ist ein Vorgang, welcher der Lactonbildung aus Ketonen mittels Persuren und Wasserstoffperoxyd analog ist. Vom chemischen Standpunkt erklrt dieser Mechanismus den biologischen Abbau des Tryptophans zu Formylkynurenin zufriedenstellend. 4 Die Anlagerungsverbindungen von Wasser oder Essigsure an -Hydroxy--indole vom Typ (a) und (b) sind Glykole, die in saurer Lsung, falls Wasserabspaltung erfolgen kann (a R2=H), in Oxindole bergehen oder in alkalischem oder neutralem Medium mglicherweise oxydative Ringspaltung erleiden; ein Seitenweg zu Derivaten des Dioxindols ist mglich, wrde aber nicht weiter zu Formylkynurenin fhren. Die Bildung von Formylkynurenin aus Tryptophan nach SchemaB wrde den enzymatischen Versuchen vonKnox undMehler gerecht. 5 Als dritter Mechanismus (SchemaC in der bersicht auf Tafel I) fr den biologischen Abbau des Tryptophans lt sich ein -Hydroperoxy--tryptophan nicht unbedingt ausschlieen. Eine solche Verbindung knnte sich direkt zu Formylkynurenin umlagern. Im Zusammenhang mit der Errterung dieser Oxydationsmechanismen werden einige neue Beziehungen und Aspekte im Stoffwechsel des Tryptophans diskutiert.
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Versuche zur Synthese von Oxindolyl-alanin (α-Oxy-tryptophan) ausgehend von Oxindol und Dioxindol, vornehmlich unter Anwendung der Mannich-Reaktion, werden beschrieben. Während mit Oxindol und seinen Derivaten keine normale Mannich-Reaktion eintrat, bildeten Diacyl-dioxindole mit Formaldehyd und sekundären Aminen glatt die erwarteten tertiären Mannich-Basen. Diese Basen setzten sich jedoch mit Formamino-malonester nicht im Sinne einer Kondensation um, sondern tauschten ihre Dialkylaminomethyl-Gruppe gegen das aktive H-Atom des Esters aus. Diese merkwürdige, bisher nur bei der Tryptophan-Synthese aus Indol und Piperidinomethyl-formamino-malonester beobachtete Austauschreaktion trat auch zwischen Diacyl-dioxindolen und Piperidinomethyl-formaminomalonester ein. Versuche, Oxindolyl-alanin aus o-Nitro-phenylessigester, o-Nitro-phenylmalonester und o-Nitro- mandelsäureester durch Mannich-Reaktion zu synthetisieren, mißlangen.
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Indole-2-one derivatives were prepared from the corrisponding isatines via one pot reduction in hydrazine hydrate.
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Sir John Cornforth's work on the synthesis of cholesterol and penicillamine, on the chemistry of oxazoles, the stereochemistry of the synthesis of alkenes, the synthesis of abscisic acid and of dibenzophospholes as mimics of enzyme action, is reviewed.
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Cross coupling reactions of lithiated 2,5-piperazinedione anions with gramine methosulfate and alkylhalides were shown to be catalyzed by copper reagents, e.g. dilithium tetrachlorocuprate and copper (I) iodide. Based on this findings, the results of the first method for preparation of racemic thaxtomins are reported. Compound 1c, chosen as a synthetic model, was prepared in five steps in 19% overall yield. The key step was reaction of the lithiated anion of sarcosine anhydride with gramine methosulfate in the presence of a catalytic amount of dilithium tetrachlorocuprate in THF. The remainder of the sequence involved protection of the indole NH, aldol condensation with 3-benzyloxybenzaldehyde, bromohydrin formation and catalytic hydrogenation.
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(+)-α-Oxy-tryptophan, das von H. Wieland und B. Witkop als Bestandteil des Phalloidins in Amanita phalloides aufgefunden worden ist, wurde durch Spaltung der d,l-Verbindung über das Brucin-Salz der N-Acetyl-Verbindung ebenso wie die (−)-Verbindung erhalten.
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2A palladium-catalyzed α-arylation of amides is reported. Intermolecular arylation of N,N-dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst. Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium catalyst. The palladium catalyst was formed in situ from Pd(dba)2 (dba = trans,trans-dibenzylidene acetone) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene). Although the intermolecular arylation of amides is less general than that reported previously for ketones, unfunctionalized and electron-rich aryl halides gave α-arylamides in 48-75% yield and N-methyl-α-phenylpyrrolidinone in 49% yield. These reactions provided the highest yields yet reported for regioselective amide arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52-82% yield. Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of dioxane, rather than THF, solvent was important for some of the amide arylations.
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The preparations of cis- and trans-1-benzylisatylidene-3-acetaldehyde, cis- and trans-1-benzylisatylidene-3-acetic acid and some derivatives are described. Structures are assigned on the basis of NMR and pKa measurements.
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Es wird bewiesen, daß bei der Kondensation von Malonester mit Thiokresylmethylen-oxindol (II; R′=H, X=S·C 6H4·CH3) diese in 2-Stellung des Oxindolrings erfolgt, was auch für die Umsetzung einiger anderer aktiver Methylenverbindungen mit Abkömmlingen des Oxymethylen-oxindols wahrscheinlich ist. Chlormethylen-oxindol (II; R′=H, X=Cl) läßt sich dagegen mit Natrium-formamino-malonester in den α-Carbäthoxy-α-formamino-β-[isatyliden-(3)]- propionsäureester (IV; R′=H, R″=NH·CHO) überführen, der durch Reduktion und Totalhydrolyse β-Oxindolyl-(3)-alanin (I) liefert. Es wird auf die Möglichkeit hingewiesen, aus dem erwähnten Zwischenprodukt IV das Dioxindolyl-alanin (XII) zu synthetisieren, das als Vorstufe des N′ -Formyl-kynurenins beim biologischen Abbau des Tryptophans in Betracht kommt.
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The stability of Trp in pure solutions and in parenteral AA formulations was evaluated with regard to typically used manufacturing processes, storage conditions and primary packaging. Therefore, thorough stability studies on Trp solutions were conducted beforehand. The applied stressing method, i.e. steam sterilization by autoclave, are chemically seen relatively mild but showed to be efficient to induce Trp degradation in the presence of oxygen. Subsequent identification, separation and characterization were challenging due to similar substance properties, numerous stereoisomers and pairs of diastereomers found amongst them. However, the identified o-aminoacetophenone compounds, Kyn and NFK, are associated with photo reactivity and have photo-oxidizing properties. Thus, best possible protection from UV-light, together with strict oxygen expulsion, are the most important criteria to impede Trp degradation after autoclaving. The identification of Trp degradation products was assisted by the compilation of a substance library, which included manifold reported and chemically plausible Trp degradation substances. The substances were classified for priority and their early or late-stage occurrence. The large number of possible substances and stereoisomers was narrowed down with the information retrieved from LC-UV/MS experiments. However, final identification was achieved by the synthesis of proposed substances as references. The following eight substances were characterized as Trp degradation substances: Kyn, NFK and three pairs of diastereomers R,R/R,S DiOia, R,R/R,S Oia and cis/trans PIC. Fig. 33 shows the proposed degradation pathway and demonstrates the close chemical relationship, which may be an explanation for the conversion of some substances into each other during the storage period. The proposed pathway brings together the results of different Trp stability and stressing studies, respectively [89, 94, 97, 98, 103, 133]. To our knowledge, the simultaneous formation of the identified degradation substances has not been reported before and especially not under the stressing conditions applied. The application of a traditional RP-HPLC method was compared to two developed IP-HPLC methods and a RP-HPLC methods using a modified perfluorinated column. Orthogonal analyses methods and especially the combination of UV and MS detection are necessary in order to indicate potentially undetected degradation substances. Main evaluation criteria were the separation performance, analyses time, reproducibility and feasibility. The best results upon assessment of all Trp degradation products, in both; pure Trp solutions and pharmaceutical formulations, were obtained by a traditional RP-HPLC. The optimized method was validated according to ICH guidelines Q2(R1) and meets the criteria of a stability-indicating HPLC-UV method. The validated method has a sufficient separation performance with an adequate selectivity indicating the Trp degradation substances next to each other and next to other AAs in finished pharmaceutical formulations. The detailed knowledge of Trp degradation and the method presented may be transferred practically to the pharmaceutical industry processing Trp-containing products. In general, the findings might contribute to the quality management of such pharmaceutical products during manufacturing and storage. Additionally, the study results provide basic information for the establishment of an impurity consideration following the ICH guidelines Q3B (R2) (impurities in new drug products) for products containing Trp. However, further development of the method applying more sophisticated detectors or more potent HPLC techniques like e.g. UHPLC and the implication of more sensitive (MS) detectors like ToF-MS would be advantageous with regard to economic and practical aspects.
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