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A concise total synthesis of the thiazoline-thiazole containing metabolite didehydromirabazole A 1 is described. The synthesis uses the unusual amino acid (R)-2-methylcysteine 20 in sequential cyclocondensations with imino ethers as key steps, viz22→32 and 37→38.
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... Natural products possess the characteristics of low toxicity, good biodegradability, and compatibility, so they have been widely used as commercial fungicides (Ma et al. 2013;, insecticides (Crouse et al. 2018;Tacoli et al. 2018), and herbicides (Duke et al. 2010). In the past years, many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with various biological and medicinal activities, including anti-HIV (Pattenden and Thom 1993), antibiotic (Zamri et al. 2003), and anticancer activity (Gududuru et al. 2005), have reported, whereas there is few report about the utilization in preventing plant disease. Recently, our research group have reported some (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with amide and ester moieties, which exhibited good and broad-spectrum antifungal activities ( Fig. 1) (Liu et al. 2019(Liu et al. , 2015. ...
To discover a novel lead structure for antiphytopathogenic fungus agent, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. They were determined by melting points, ¹H NMR, ¹³C NMR, and elemental analysis (EA). The biological activity results revealed that these title compounds possessed antifungal and insecticidal activities. Some title compounds against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum displayed moderate to good antifungal activities at 50 mg/L, especially, compounds 6b and 6p displayed good and broad-spectrum antifungal activities. The structure activity relationships were discussed. A 3D-QSAR model was established based on the antifungal activity against Phytophthora capsici, indicating that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Hence, structure optimization based on the CoMSIA model was performed to find compound 6p with excellent activity against Phytophthora capsici, and the EC50 values of compound 6p were comparable to those of chlorothalonil. Furthermore, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was considerable to that of chlorantraniliprole. Therefore, compound 6p can be used as a novel lead structure for antiphytopathogenic fungus and insecticidal agent development.
... (R)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid, as a natural product representative of 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives, has been confirmed to possess anticancer activity for L1210 cell lines in vitro . In the past years, researchers have reported many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with a variety of biological activities in medicinal chemistry, including antibiotic , anti-HIV , and anticancer activities . However, few researches about the application in plant disease prevention have been reported. ...
A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50 values of (R)-N’-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R1 position, as well as a proper hydrophilic and electron-donating group in the R2 position, could improve the antifungal activity against Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N’-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as effective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata.
Triphenylcarbenium ions (trityl cations: [RPh]3C+) are broadly identified organic compounds, because of their several uses, such as protective group, a catalyst for C–C bond formation, dye chemistry, carbohydrate chemistry, oxidation and reduction reagent, polymer and peptide synthesis, chiral catalyst, activity-based probes, and photochemical reactions. Trityl cations have also been applied as neutral Lewis acids in different chemical reactions. Possibly, the trityl cation is most widely used in hydride abstraction reactions both in the study of mechanisms transformations (organometallic and organic) and in organic syntheses. Ph3C+ is also extensively applied as very efficient activators and as one-electron oxidants for olefin polymerization reactions. In this review, we explain applications of trityl moieties in chemical processes and synthesis.
The absolute configuration of curacin A was determined as (2R,13R,19R,21S)-1 by comparison of degradation products 2 and 3 with the same materials prepared by asymmetric synthesis. The total synthesis of 1 was completed from (1R,2S)-2-methylcyclopropanecarboxylic acid (8) and the amino alcohol derivative 46. The latter was prepared from 4-pentynal (14) and the Garner aldehyde (43). Asymmetric allylation of 14 followed by methylation of the derived alcohol 16 gave 17, which was subjected to zirconation−iodination to yield 18. The latter was coupled to the vinyl boronate 21, prepared from 4-pentynyl acetate (20), in the presence of Pd(0), and the resultant trienol 22 was converted to phosphonium iodide 24. Wittig reaction of the ylide from 24 with 43 afforded tetraene 44 which produced 45 upon methanolysis. The mesylate 46 was advanced to thioester 48 either by direct coupling with potassium thiolate 47 obtained from (−)-8 or indirectly via 49. The amino thioester liberated from 48 underwent thermal cyclization to give (+)-curacin A.
Die modulare Synthese des marinen Naturstoffs Largazol und abgeleiteter synthetischer Analoga wird beschrieben. Largazol wurde nach einer Synthese mit neun linearen Stufen in 19 % Gesamtausbeute erhalten. Aktivitätstests belegten die Notwendigkeit der Thiobutenyl-Gruppe für eine antiproliferative Wirkung.
From cultures of Yersinia enterocolitica H1852, an iron-complexing and iron-transporting compound named yersiniabactin was isolated. The structure of the siderophore was determined by a variety of spectroscopic methods, including 2D NMR experiments on the metal-free ligand as well as its gallium complex. The metal-free ligand, derivatives, as well as iron and gallium complexes were examined by high-resolution FAB-MS, API-MS, API-MS/MS and GC-MS. The novel siderophore contains a benzene and a thiazolidine ring, as well as two thiazoline rings (Figure 1). Its stereochemistry is noteworthy for the presence of five chiral centers, one of which is considerably epimerized. The compound forms stable complexes with trivalent cations such as ferric iron and gallium.
The thiazole-thiazoline fragment of the marine natural product largazole, a potent histone deacetylase 1 inhibitor, has been synthesized in five steps. The methodology provides rapid access to thiazole-4-carbonitrile, thiazole-4-carbimidate, thiazole-oxazoline, and other thiazole-thiazoline derivatives that are important intermediates in the total synthesis of many natural products with important biological properties.
A modular synthesis of the marine natural product largazole and related synthetic analogues is described. Largazole was prepared in 19% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity. (Chemical Equation Presented).
An overview of the chemical and physical properties of 2-thiazolines is studied, including new methodologies for their preparation, and applications. 2-Thiazoline derivatives are prepared from either β-amino thiols or β-amino alcohols. Condensation of β-amino thiols with nitriles or carboxylic acid derivatives is a straight forward route to 2-thiazolines. The new thiazolines are efficiently prepared either from amino thiols or from amino alcohols. New synthetic methodologies, which use the convenient thiocarbonyl, provide a fantastic opportunity to create structural diversity and efficiently tune the properties of these compounds. The first study using thiazolines was reported by Helmchen in 1991, where he studied the efficiency of C 2-symmetric bis(thiazolines) in the rhodium-catalyzed asymmetric hydrosilylation of acetophenome. Thiazolines should be considered as a new family of compounds and not only as sulfur analogues of oxazolines.
Microcin B17 (McB17), the first known gyrase inhibitor of peptidic nature, is produced by ribosomal synthesis and post-translational modification of the 69-residue precursor protein by an Escherichia coli strain. To elucidate the chemical structure of the mature 43-residue peptide antibiotic, fermentation and purification protocols were established and optimized which allowed the isolation and purification of substantial amounts of highly pure McB17 (non-labelled, 15N-labelled and 13C/15N-labelled peptide. By ultraviolet-absorption spectroscopy. HPLC-electrospray mass spectrometry and GC-mass spectrometry, amino acid analysis, protein sequencing, and, in particular, multidimensional NMR, we could demonstrate and unequivocally prove that the enzymic modification of the precursor backbone at Gly-Cys and Gly-Ser segments leads to the formation of 2-aminomethylthiazole-4-carboxylic acid and 2-aminomethyloxazole-4-carboxylic acid, respectively. In addition, two bicyclic modifications 2-(2-aminomethyloxazolyl)thiazole-4-carboxylic acid and 2-(2-aminomethylthiazolyl)oxazole-4-carboxylic acid were found that consist of directly linked thiazole and oxazole rings derived from one Gly-Ser-Cys and one Gly-Cys-Ser segment. Analogous to the thiazole and oxazole rings found in antitumor peptides of microbial and marine origin, these heteroaromatic ring systems of McB17 presumably play an important role in its gyrase-inhibiting activity, e.g. interacting with the DNA to trap the covalent protein-DNA intermediate of the breakage-reunion reaction of the gyrase.
The scope and limitations of TiCl(4)-mediated Delta(2)-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the stereochemical outcomes vary on the basis of structural considerations and reaction conditions (22-99% ee). Racemization at the C(2)-exomethine position limits the utility of this method for the formation of a thiazoline within a peptide. Treatment of a tritylated Cys-Cys dipeptide with TiCl(4) afforded the corresponding thiazole-thiazoline heterocycle 12 (38% yield, 97% ee).
An elaborate array of structurally-novel and biologically-active cyclic peptides and depsipeptides are found in blue-green algae (cyanobacteria). Several of these compounds possess structures that are similar to those of natural products from marine invertebrates. Most of these cyclic peptides and depsipeptides, such as the microcystins and the lyngbyatoxins, will probably only be useful as biochemical research tools. A few, however, have the potential for development into useful commercial products. For example, cryptophycin-1, a novel inhibitor of microtubule assembly from Nostoc sp GSV 224, shows impressive activity against a broad spectrum of solid tumors implanted in mice, including multidrug-resistant ones, and majusculamide C, a microfilament-depolymerizing agent from Lyngbya majuscula, shows potent fungicidal activity and may have use in the treatment of resistant fungal-induced diseases of domestic plants and agricultural crops.
Previously, a method for the stereoselective synthesis of beta-lactams, starting from 2H-Delta(2)-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-Delta(2)-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 --> 78 degrees C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 --> 64 degrees C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different Delta(2)-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.
Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.
Reaction of serine derived 1-alkoxy-2-azadienes with dehydroalanine derived dienophiles results in Diels-Alder reaction and aromatisation to give 2,3,6-trisubstituted pyridines, thereby establishing the viability of the proposed biosynthetic route to the pyridine ring of the thiopeptide antibiotics originally proposed by Bycroft and Gowland.
[reaction: see text] In developing a synthetic entry to the thiazoline-containing domain of the apratoxin natural products, we converted vicinal azido-thiolesters into 2,4-disubstituted thiazolines via sequential one-pot Staudinger reduction/aza-Wittig reaction. This method of de novo thiazoline formation provides a mild and versatile process that is particularly well suited to acid-sensitive substrates.
(1R)-(+)-2,10- and (1S)-(-)-2,10-camphorsultam were acylated with ethyl 2-phenylthiazoline 4-carboxylate to afford (+)- and (-)-2-phenylthiazolinylcamphorsultam, which were stereoselectively alkylated with MeI in the presence of n-BuLi. Alkylation of these phenylthiazolinylcamphorsultams occurred from the beta-face rather than alpha-face, resulting in the formation of (S)-alpha-methylcysteine from (1R)-(+)-2,10-camphorsultam and (R)-alpha-methylcysteine from (1S)-(-)-2,10-camphorsultam after acidic hydrolysis. Subsequent protection of the side chain thiol group with trityl alcohol and alpha-amine function with Fmoc-OSu furnished fully protected (S)- and (R)-N-Fmoc-S-trityl-alpha-methylcysteine in overall 20% yield.
The preparation and resolution of a series of axially chiral quinazoline-containing ligands is described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation, the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles derived from the racemic phosphinamines and (+)-di-mu-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C2,N]dipalladium(II) were separated by fractional crystallization. The configuration of the resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving excellent conversions, good to complete regioselectivities, and the highest enantioselectivities obtained to date for several members of the vinylarene class, including cis-beta-methylstyrene (97%), cis-stilbene (99%), and indene (99.5%).
The new total synthesis of the 4-methylthiazoline-based natural product didehydromirabazole A, produced by the blue green alga Scytonema mirabile, shows that its stereostructure is as shown in formula (12).
An approach to 2,4,5‐substituted thiazoles containing coumarins were synthesized via Intramolecular Knoevenagel condensation–cyclization reaction using triethylamine (TEA) as a base and are confirmed by spectroscopic analysis. In‐vitro screening, molecular docking (performed to preferred binding mode and supports the interaction of thiazole‐coumarin derivatives with enzyme) studies are reported. A detailed study subsidized by theoretical calculations directed us to determine that: an intact thiazole and coumarin rings appear to be needful for a strong antifungal activity, dis similarly determined by the substituents on coumarin and change in nitrogen rings. All the derived conjugates are fungicide and enhancing their antifungal inhibition due to different substitutions. The presence of flexible connecting N‐substitutions found to be required for antifungal inhibition, although its ring size shows reciprocally with antifungal nature in most fungi. Some active derivatives did not found effective inhibitor against bacterial strains, indicating that their inhibition is selective to pathogenic fungi and also they are non‐toxic at MIC concentrations.
Heteropolyacid anchored on SBA-15 functionalized with 2-aminoethyl dihydrogen phosphate (SBA-15@AEPH2-HPA) was synthesized as a novel and highly efficient heterogeneous mesoporous catalyst. Characterization of the as-synthesized catalyst was successfully performed using various techniques such as FT-IR, BET, small-angle XRD, SEM, EDX, TEM, TGA, ICP-OES and elemental analysis. The new catalyst revealed a superb catalytic activity towards the one-pot synthesis of a wide verity of trisubstituted 1,3-thiazole derivatives. This protocol involved the three-component reactions of arylglyoxals, cyclic 1,3-dicarbonyls and thioamides under mild reaction conditions. Surprisingly, the current methodology is far superior to the only literature precedent used in this regard. The most promising features which highlight the presented approach are: furnishing a very important class of pharmaceutically and biologically active 1,3-thiazoles in excellent yields within short reaction times, mildness of the reaction conditions, using water as the reaction media and facile catalyst reusability for at least nine successive runs without any appreciable loss of its activity. Importantly, the small-angle XRD analysis and TEM images of the 9th recovered catalyst clearly proved the privileged durability and stability of the introduced catalytic system, under the applied reaction condition.
Biotechnological uses of cyanobacteria for their unique products envisage improving the product quality through genetic manipulation. A case for more research in the area of cyanobacteria is made in this article by summarizing multifaceted developments on the potential of cyanobacteria for their possible use in mariculture, food, feed, fuel, fertilizer, colourant, secondary metabolites including vitamins, toxins, enzymes, pharmaceuticals, pharmacological probes and pollution abatement.
Roz Anderson is a graduate of the University of Newcastle, where she obtained both her B.Sc. (1984) and Ph.D. (for work on the chemistry of cobaloximes, under the supervision of Prof. Bernard Golding) degrees. She then moved to Sunderland University to a post-doctoral position with Prof. Jeff Brown in the School of Pharmaceutical Sciences. In 1990 she was appointed to a Lectureship in Organic Chemistry and was promoted to Senior Lecturer in 1993 and Principal Lecturer in 2003. Her research interests include; the synthesis of novel chromogenic agents for enhanced bacterial detection, the investigation into the rôle of tryptophan hydroxylase in autism and the possible rôle of environmental factors in the symptomology, the design, and synthesis of improved cysteamine prodrugs, and molecular modeling in drug design and reaction mechanisms
A systematic survey of conditions and substrates for the formation of 2,4,4-trisubstituted thiazoline rings is presented. The substitution patterns of these thiazolines is particularly relevant for the synthesis of the tantazole, mirabazole, and thiangazole classes of natural products, which contain a linear array of these heterocycles. Methods for the formation of these thiazolines from 2-methyl cysteines and 2-halomethylalanines are discussed.
A range of 2-aryl and 2-alkyl quinazolinones have been prepared in moderate to good yields from the reaction of anthranilic acid and the appropriately substituted imidate in a facile, mild, onepot procedure. Subsequent reaction with phosphorus oxychloride afforded the corresponding 4-chloro-2-substituted quinazolines, which are useful synthetic intermediates, in good to high yields. Product isolation was facilitated by the development of work up procedures for both reactions that did not include purification by column chromatography.
Vince S. C. Yeh received his BS degree (1994) from the University of British Columbia where he participated in undergraduate research under the late Professor L. Weiler. He completed PhD (2001) from the University of Alberta under the guidance of Professor D. L. J. Clive, where he studied the asymmetric syntheses of alkaloids. After postdoctoral research (2003) with Professor B. M. Trost at Stanford University on asymmetric aldol catalysts, he joined Abbott Laboratories as a Senior Research Chemist working in the area of metabolic diseases. His research interests include drug discovery, asymmetric synthesis, and natural products.
The formation of thiazolines from beta-hydroxythioamides under TsCl/Et(3)N, SOCl2, and Mitsunobu conditions leads to extensive epimerization at the C(2) exo methine position. In contrast, thiazolines of >94%, diastereomeric purity are isolated when the Burgess cyclodehydration protocol is applied.
A clean, efficient and catalyst free multicomponent domino reaction of arylglyoxals, cyclic 1, 3-dicarbonyls and thioamides in aqueous medium under microwave conditions is reported. A wide variety of trisubstituted thiazole compounds can be synthesized in good to very good yields using this green protocol. The salient features of this methodology are: catalyst-free reaction, water as reaction medium, short reaction time, good yields, use of microwave heating and no harmful by-products.
The total synthesis of the cinnamyl-oxazole substituted tris-thiazoline containing metabolite (−)-thiangazole (1) is described. The synthesis is based on elaboration of the R-2-methylcysteine derived bis-thiazoline nitrile (5) and oxazole (6) intermediates, followed by a cyclocondensation reaction between (5) and (6), and treatment of the resulting tris-thiazoline oxazole ester (16) with methylamine.
A microwave-assisted hydrolysis of thiazolidines was developed for the synthesis of enantioenriched α-alkylcysteines. Under optimized conditions, the efficiency of the reaction can be considerably improved and the scope significantly broadened as compared to previously described processes. This approach is shown to be applicable to the multi-gram scale using a high-throughput microwave system.
Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC50 values less than 1 muM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.
The partial synthesis of 54 derivatives of thiangazole A (1a), a new polythiazoline antibiotic from Polyangium spec. (myxobacteria), is described. Derivatives with chemical modification of the carboxamide group in the oxazole region were prepared either by N-alkylation to amides 5–14 or by methanolysis to ester 15, and its transformation products 16, 19, 20. Oxidation of the C-5 methyl group of 1a with molecular oxygen led to the hydroxymethyl derivative 21, and two by-products lacking the C-5 methyl group (22), or the entire oxazole ring (23). Key intermediate for analogues with modifications in the styryl region is the aldehyde 27, obtained by direct cleavage of the C-21/C-22 double bond. 27 was transformed into the oximes 37–42 and by Wittig reaction to (21Z)-thiangazole (43) and analogues 44–46 with proton and alkyl residues replacing phenyl. 21,22-Didehydrothiangazole (50) was synthesized in a multi-step reaction from 27 via the 20-alkinyl intermediate 49. The insecticidal activities and inhibition of the respiratory chain (complex I) by the thiangazole analogues were determined and compared with the natural product.
This document is part of Subvolume D3 `Chemical Shifts and Coupling Constants for Carbon-13: Heterocycles' of Volume 35 `Nuclear Magnetic Resonance (NMR) Data' of Landolt-Börnstein Group III `Condensed Matter'
The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.
L-Cysteinesulfinate, a quantitatively important catabolite of L-cysteine, is a substrate of both cysteine-sulfinate decarboxylase and glutamate-oxaloacetate transaminase. The former enzyme initiates a pathway leading to taurine; the latter enzyme forms β-sulfinyl-pyruvate, which spontaneously decomposes to pyruvate and SO2. In the present studies, the in vivo partitioning of cysteinesulfinate between these two pathways was evaluated by administering to mice L-[1-14C]cysteinesulfinate, which is metabolized to 14CO2 by both pathways, or L-[3-14C]cysteinesulfinate, which is converted to 14CO2 only if taurine is not formed. Within 6 h, respiratory 14CO2 accounted for 90% of the [1-14C]cysteinesulfinate injected, whereas only 18% of administered [3-14C]cysteinesulfinate was recovered as 14CO2. When the data are corrected for differences in the formation of 14CO2 from [1-14C]- and [3-14C]pyruvate and for a small formation of 14CO2 from radiolabeled hypotaurine, it is concluded that ~85% of administered cysteinesulfinate is decarboxylated to hypotaurine, whereas ~15% is transaminated. Of the hypotaurine formed, ~90% is oxidized to taurine. β-Methylene-DL-aspartate, an irreversible inhibitor of glutamate-oxaloacetate transaminase was given to mice with the expectation that conversion of cysteinesulfinate to hypotaurine would be increased. Surprisingly, the extent of cysteinesulfinate transamination increased about 3-fold. Additional studies indicate that β-methyleneaspartate is a potent, irreversible inhibitor of purified rat liver cysteinesulfinate decarboxylase and that inactivation of the decarboxylase predominates over inactivation of the transaminase in vivo. Highly purified cysteinesulfinate decarboxylase is also shown to decarboxylate L-aspartate to β-alanine and, very slowly, glutamate to γ-aminobutyrate. The enzyme is not active toward α-methylcysteinesulfinate or α-methylaspartate; α-methyl-DL-[1-14C]cysteinesulfinate is not metabolized by the mouse.
Metabolites of Microorganisms. FerrithiocinThe strain Tü 1998 from Streptomyces antibioticus produces besides the indicator antibiotics β- and γ-rubromycins a new sulfur containing metabolite. This metabolite, called ferrithiocin, has been isolated in the form of a iron complex. The structure 1 of the iron-free compound was elucidated by spectroscopic studies and chemical degradation.
The Mitsunobu reaction was efficiently used to introduce oxazolines and thiazolines in the peptide backbone. The reaction proceeded from β-hydroxy α-amino acid-containing peptides at room temperature in 58-72% isolated yields.
Three tantazole-related compounds, viz. didehydromirabazole A (1) and mirabazoles B (2) and C (3), have been isolated as minor components from Scytonema mirabile (Dillwyn) Bornet (strain BY-8-1) and their structures elucidated.
Cyclothiazomycin is a novel renin inhibitor produced by .NR0516 (IC50 1.66μM). Its molecular formula was determined to be C59H64H18O14S7 (MW .1472) based on high-resolution FAB mass and NMR spectroscopy. Five fragments of cyclothiazomycin containing thiazole, thiazoline, heterocyclic chromophore were clarified by extensive 2D-NMR experiments.
Total Synthesis of antibiotic althiomycin has been achieved starting from D-cysteine. The imide bond between thiazoline and the pyrrolinone part was constructed by coupling reaction of sodium salt of pyrrolinone with cysteine active ester or by photoreaction with diketene. The hydroxymethyl group attached on the carbon adjacent to C-2 of the thiazoline ring, was introduced by aldol condensation posterior to the thiazoline ring formation. The thiazole part was introduced in a final step in whole process of the total synthesis of the antibiotic. The synthetic althiomycin was identical with the natural antibiotic in all respects.
A protected heptapeptide, the formyl-L-isoleucyl-ε-benzyloxycarbonyl-L-lysyl-δ-5-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-im-benzyl-L-histidyl-L-aspartic acid α-methyl-β-benzyl ester, was synthesized by the azide method and the carbodiimide method. It is an intermediate peptide for the total synthesis of the antibiotic bacitracin A, the structure of which is still ambiguous at a few points. β-Benzyl benzyloxycarbonyl-L-aspartate was prepared by a novel method similar to that used in the synthesis of γ-benzyl glutamate. The α-methyl-β-benzyl L-aspartate prepared could be useful in the synthesis of branched aspartic acid peptide. Phenomena of dimorphism were observed in crystals of δ-tosyl-D-ornithine and δ-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanine ethyl ester hydrobromide, and two crystal forms of each compound were isolated in pure states.
Mirabimide A, the major imide from the terrestrial blue-green alga Scytonema mirabile (Dillwyn) Bornet (strain BY-8-1), is N-[2-(N,N-dimethylleucyl)oxy-3-methylpentanoyl-N-methylvalyl-prolyl]-4-methoxy-5-isopropyl-3-pyrrolin-2-one. Mirabimides B–D are the valyl, 2-oxy-3-methylbutanoyl, and N-acetyl-N-methylleucyl analogs, respectively. The absolute configurations of the five asymmetric carbons in the mirabimides are proposed to be all S, but the assignments for the dimethylleucine units in A–C and the hydroxyacid units in B–D are tentative.
Using a biological screening with a HIV-1/MT-4 cell assay indicating antiviral activity and cell toxicity, we detected and isolated a new inhibiting metabolite from gliding bacteria, thiangazole (1). The structure of 1 was determined by spectroscopic methods to be a tris(thiazoline) derivative, showing a remarkable similarity to tantazole B (2). Chemical degradation and comparison with a synthetically prepared reference compound as well as with the degradation product from 2 furnished the (5R,8S,11S) configuration of the asymmetric centers in 1.
A concise total synthesis of the thiazole-thiazoline based metabolite (-)-didehydromirabazole A (2), a cytotoxic alkaloid isolated recently from the blue-green alga Scytonema mirabile, is described which uses sequential cyclocondensation reactions with methyl (R)-2-methylcysteine hydrochloride (5) as key steps, viz6 → 7 and 10 → 11.
Certain thiazoles are obtained via dehydrative cyclization of the corresponding cysteinyl peptides and oxidation of the resulting thiazolines with NiO2; the biomimetic syntheses of two natural products are reported, as is the potential of NiO2 as an oxidant for other partially reduced heterocycles.
The lipophilic extract of the cultured terrestrial blue-green alga Scytonema pseudohofmanni Bharadwaja contains five novel macrolides, scytophycins A (1), B (2), C (3), D (4), and E (5), which exhibit cytotoxicity and antifungal activity. The structures of 1-5 have been determined mainly from spectroscopic data. The relative stereochemistries of the scytophycins are based on an X-ray crystallographic analysis of a transformation product of scytophycin C (8) and comparison of the 1H and 13C NMR spectra of 1-5. The absolute stereochemistries of the scytophycins have been deduced from a circular dichroism study of the dibenzoate ester 16, obtained in five steps from scytophycin B, and comparison of the CD curves of 1-5. These novel secondary metabolites appear to be biogenetically related to the marine natural products swinholide A, ulapualides A and B, and kabiramide C.
An aerial form of Scytonema mirabile (Dillwyn) Bornet, designated strain number BY-8-1, has been found to contain six novel isonitriles, viz. mirabilene isonitriles A-P (7-12), which are mildly cytotoxic and antimicrobial. The gross structures of 7-12 were determined by detailed spectral analysis. The relative and absolute stereochemistry of 7-12 were solved by chemical degradation and direct comparison of degradation products with synthetic samples; mirabilene-A isonitrile (7), for example, was degraded to methyl (3R,5R,7S,9S)-3,5,7,9-tetramethoxy-10-oxoundecanal (15) and isopropyl (S)-3-trifluoroacetamidobutyrate (14), which indicated that the absolute configurations of C-4, C-6, C-8, C-10, and C-16 in 7 were all S.
Treatment of the N-formyl derivative of the thiazolidine adduct derived from (R-cysteine methyl ester hydrochloride and pivalaldehyde, with LDA-DMPU at −90°C, followed by reaction with iodomethane produces the corresponding methylated thiazolidine containing the methyl and t-butyl groups virtually exclusively anti- to one another. Hydrolysis in the presence of 5M HCl then affords (R-2-methylcysteine hydrochloride in excellent yield and enantiomeric purity. A range of other 2-alkyl substituted cysteines of excellent optical purity are prepared by this modification of Seebach's “self-reproduction of chirality” protocol.
Anguibactin (1), a novel siderophore isolated from the fish pathogen Vibrio anguillarum 775 (pJM1), has been identified as ω-N-hydroxy-ω-N-[[2′-(2″,3″-dihydroxyphenyl) thiazolin-4′-yl]carboxy]histamine. The structure determination was based on (i) single-crystal X-ray diffraction studies of its anhydro derivative (2), (ii) 1H and 13C NMR spectroscopy, (iii) FAB mass spectrometry, and (iv) chemical degradation. Anhydroanguibactin (2) crystallizes in the monoclinic space group C2/c, a = 22.71 (5) Å, b = 8.052 (6) Å, c = 15.879 (18) Å, β = 95.72 (9)°, V = 2889.2 Å3, and Z = 8. The structure has been determined from 2029 diffractometer data and refined to a final R = 0.048. Spectroscopic results have shown that anguibactin (1) differs from 2 by having (i) a thiazoline ring instead of a thiazole ring and (ii) a hydroxyl group on the peptide N atom of the histamine residue. Anguibactin belongs to a unique structural class of its own, with its backbone derived from ω-N-hydroxyhistamine, cysteine, and 2,3-dihydroxybenzoic acid. The structure of another related compound, copurified with anguibactin, was identified as 2-(2′,3′-dihydroxyphenyl)thiazoline-4-carboxylic acid methyl ester (3).
An iron-binding compound was isolated from ethyl acetate extracts of culture supernatant fluids of Pseudomonas aeruginosa and was purified by successive paper and thin-layer chromatographic procedures. The purified compound was characterized by UV, visible, infrared, and fluorescence spectroscopy. The compound possesses phenolic characteristics, with little or no similarity to dihydroxybenzoates and no indication of a hydroxamate group. P. aeruginosa synthesized the compound during active growth in culture media containing less than 5 X 10(-6) M added FeCl3. When added to iron-poor cultures of P. aeruginosa, the compound promoted the growth of the bacterium and also reversed growth inhibition by the iron chelator ethylenediamine-di-(o-hydroxyphenylacetic acid).
Aus dem leicht synthetisierbaren Thiazolin (Ia) sind die Amide (Ib) bzw. (Ic) zugänglich, die sich über die (zweckmäßig nicht isolierten) Bromide (IIa) bzw. (IIb) (jeweils Isomerengemische) zu den β-Lactam-thiazolinen (IIIa) bzw. (IIIb) cyclisieren lassen.
Tolytoxin , the major cytotoxin associated with Scytonema mirabile strain BY-8-1, Scytonema burmanicum strain DO-4-1 and Scytonema ocellatum strains DD-8-1, FF-65-1, and FF-66-3, has been shown to be 6-hydroxy-7-O-methylscytophycin B. Minor amounts of three other new cytotoxic scytophycins, 6-hydroxyscytophycin B , 19-O-demethylscytophycin C , and 6-hydroxy-7-O-methylscytophycin E , have also been isolated from these cyanophytes. The gross structures and stereochemistry are based on nmr and cd analysis and on comparison with scytophycins A-E.
The isolation and structures of a new patellamide (patellamide D) and two new lissoclinamides (lissoclinamides 4 and 5) from the aplousobranch ascidian Lissoclinum patella are described. Structures were determined largely by using two-dimensional NMR techniques and mass spectrometry. These peptides and other members of the patellamide and lissoclinamide families that have been reported previously are found within the obligate algal symbiont of the genus Prochloron. The cytotoxicities of the compounds toward fibroblast and tumor cell lines are reported. One of these compounds, lissoclinamide 4, is markedly more toxic than other members of the family. Structure-activity relationships are discussed.
The hydrolysis of 13 Δ2-thiazolines has been investigated in the pH range 0-6 at 30°. Analysis of the characteristic, bell-shaped rate-pH profiles as well as the effect of variation in the polar nature of aryl substituents in the 2-position of the thiazoline nucleus support the general validity of a previously proposed mechanism for thiazoline hydrolysis. The rate of hydration of thiazolines has been found to vary by a factor of 38,000 over the series of compounds examined. For ten 2-arylthiazolines, with or without 4-substitution, a linear relationship between the logarithm of the hydrolysis rate constant and the pK of the thiazolinium ion has been noted. A parallel relationship appears valid for 2-melhylthiazolines, which are about 250 times more reactive than 2-arylthiazolines of the same pK. The observation of a constant rate of hydrolysis of 2-methylthiazoline at alkaline pH (78°) is discussed.