First total synthesis of the 7,3'-linked naphthylisoquinoline alkaloid ancistrocladidine

[structure: see text] The first total synthesis of the rare 7,3'-linked naphthylisoquinoline alkaloid, ancistrocladidine, has been completed. The key feature of the synthesis is the formation of the extremely hindered biaryl linkage by Pinhey-Barton ortho-arylation of a naphthol with an aryllead triacetate. The biaryl aldehyde formed is elaborated in 10 steps to form a 1:1 mixture of ancistrocladidine and its atropisomer. Recrystallization of the mixture afforded ancistrocladidine, which was identical in all respects to the reported data.     

Synthesis of spiro[benzopyrazolonaphthyridine-indoline]-diones and spiro[chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water

The synthesis of spiro[benzo[h]pyrazolo[3,4-b][1,6]naphthyridine-7,3′-indoline]-2′,6(5H)-diones and spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6(6aH,10H)-diones via a one-pot, three-component reaction of 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one, isatins and 1H-pyrazol-5-amines in water is reported.     

First Atroposelective Total Synthesis of Enantiomerically Pure Ancistrocladidine and Ancistrotectorine

The first regio‐ and stereoselective total synthesis of the axially chiral 7,3′‐coupled naphthylisoquinoline alkaloids ancistrocladidine ( 1 ) and ancistrotectorine ( 2 ) has been described. Both possess a 7,3′‐coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis‐array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the “lactone method”: the two molecular halves, which were activated in an “inverse‐halogenated” form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold.     

Total synthesis of the 7,3'-linked naphthylisoquinoline alkaloid ancistrocladidine

The first total synthesis of ancistrocladidine, a rare 7,3'-linked naphthylisoquinoline alkaloid, has been completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with an aryllead triacetate. Initial efforts were focused on the generation of a heteroaryl lead species, which would have allowed a convergent synthesis to be developed. However, it was not possible to generate such a lead species. A simpler aryl lead triacetate was prepared and reacted. The resulting biaryl aldehyde was elaborated in 10 steps to form a 1:1 mixture of ancistrocladidine and its atropisomer. Recrystallization of the mixture afforded ancistrocladidine, which was identical in all respects to the reported data.     

Studies on Flavans. III. The Total Synthesis of (±)-7,4′-Dihydroxy-3′-methoxyflavan, (±)-7,3′-Dihydroxy-4′-methoxyflavan,and (±)-7,4′-Dihydroxyflavan

Abstract

The first total synthesis of (±)-7,3′-dihydroxy-4′-methoxyflavan (1) and (±)-7,4′-dihydroxy-3′-methoxyflavan (2), along with the synthesis of (±)-7,4′-dihydroxyflavan (3), three naturally occurring flavans, were described. The key step is the cyclization of 1,3-diaryl-1-propanol by BF₃·Et₂O.     

Synthesis of glucosylspiro-oxindole derivatives via one-pot three-component cycloaddition of azomethine ylides

Highly regio- and stereoselective synthesis of glucosylspiro-oxindole/acenaphthenone derivatives was accomplished through 1,3-dipolar cycloaddition (1,3-DC) reaction. The glucosyl α,β-unsaturated-7,3-lactone (a sugar lactone) derived from d-glucose was used as a chiral dipolarophile in 1,3-DC reaction for the first time. The azomethine ylides generated from sarcosine/l-proline/thiazolidine-4-carboxylic acid/piperidine-2-carboxylic acid with isatin and acenaphthoquinone were trapped by the sugar lactone to give a series of glucosylspiro-pyrrolidine derivatives in good yields.     

Flavones and Cytotoxic Constituents from the Stem Bark of Muntingia Calabura

Two new flavones, 8‐hydroxy‐7,3′,4′,5′‐tetramethoxyflavone and 8,4′‐dihydroxy‐7,3′,5′‐trimethoxyflavone, together with thirteen known compounds have been isolated from the stem bark of Muntingia calabura. The structures of two new compounds were determined through spectral analyses. Among the isolates, 8‐hydroxy‐7,3′,4′,5′‐tetramethoxyflavone, 8,4′‐dihydroxy‐7,3′,5′‐trimethoxyflavone, and 3‐hydroxy‐1‐(3,5‐dimethoxy‐4‐hydroxyphenyl)propan‐1‐one exhibited effective cytotoxicities (ED₅₀ values = 3.56, 3.71, and 3.27 μg/mL, respectively) against the P‐388 cell line in vitro.     

Catalyst‐Free Convergent Approach for the Synthesis of Spiro[imidazo[2,1‐b][1,3]oxazine‐7,3′‐indoline

Strategies to address mounting environmental concerns with current approaches include an operationally simple and highly efficient one‐pot three‐component approach for the synthesis of spiro[imidazo[2,1‐b][1,3]oxazine‐7,3′‐indoline derivatives, which has been developed via Huisgen zwitter ion intermediate. The significant advantages of this protocol are short reaction time, excellent yields, and facile formation of three new bonds in one operation from easily available starting materials.     

Reaction pathways to dimer in polystyrene pyrolysis: A mechanistic modeling study

A detailed mechanistic model for polystyrene pyrolysis was created that built on a modeling framework developed in our previous work and was used to probe three competing pathways to dimer formation: benzyl radical addition, 1,3-hydrogen shift, and 7,3-hydrogen shift, based on recent literature reports. To incorporate the chemistry involved in the 7,3-hydrogen shift pathway, the 1,7- and 7,3-hydrogen shift reaction families were added to the model. The updated version of the model tracks 75 species and over 3500 reactions. Rate parameters for all families were specified based on our previous work, more recent literature reports, and regression against limited experimental data. The model was able to accurately predict the experimental results for polystyrene pyrolysis for different reactor configurations for a temperature range of 100 °C and two orders of magnitude of initial molecular weight for experimental data collected in our own lab and from Bouster and coworkers and Bockhorn and coworkers. The results from our model were studied using net rate analysis to gain insight into the competitiveness of the various reaction pathways to dimer formation. The net rate analysis demonstrated that 7,3-hydrogen shift is the dominant reaction pathway to dimer formation at the temperatures studied. Benzyl radical addition becomes a more competitive reaction pathway as the temperature increases, which is caused predominantly by an increase in the benzyl radical concentration with increasing temperature. Overall, it is quantitatively shown that both 7,3-hydrogen shift and benzyl radical addition are important pathways for dimer formation, with their relative competitiveness influenced by temperature.     

Simple and Clean Procedure for Three‐Component Syntheses of Spiro{pyrido[2,1‐b]benzothiazole‐3,3′‐indolines} and Spiro{thiazolo[3,2‐a]pyridine‐7,3′‐indolines} in Aqueous Medium

A simple and efficient one‐pot three component synthesis of spiro{pyrido[2,1‐b]benzothiazole‐3,3′‐indoline} and/or spiro{thiazolo[3,2‐a]pyridine‐7,3′‐indoline} derivatives were carried out by the reaction of 2‐mercaptoaniline and/or mercaptoacetic acid, malononitrile, and a series of 2‐oxoindoline‐3‐ylidines in aqueous medium. This method is of great value because of its environmentally benign character, high yield processing, and easy handling.     

Two new prenylflavanones from Erythrina sigmoidea

Two new prenylflavanones named sigmone and sigmotriol have been isolated from the stem bark of Erythrina sigmoidea along with two known constituents 8-(3"-methylbut-2"-enyl)-7,3',4'-trihydroxyflavanone and 7,3',4'-trihydroxyflavanone. Their structures were elucidated by spectroscopic methods.     

A novel three-component method for the synthesis of spiro[chromeno [4′,3′:4,5] pyrimido[1,2-b] indazole-7,3′-indoline]-2′,6(9H)-dione

A green, efficient, and rapid procedure for the synthesis of novel spiro[chromeno[4′,3′:4,5] pyrimido[1,2-b]indazole-7,3′-indoline]-2′,6(9 H)-dione derivatives has been developed by one-pot condensation of 4-hydroxy-2H-chromen-2-one, isatin, and 1H-indazole-3-amine, in the presence of acetic acid in EtOH. This method has the advantages of operational simplicity, and high yield of products via a simple experimental and work-up procedure as compared to the conventional methods. The reaction mechanism and substrate scope of this novel reaction is briefly discussed.     

An efficient synthesis of highly functionalized dinucleotide cap analogs

An efficient synthesis of new cap analogs containing aminoallyl linkers such as m⁷G[5′]pppp[5′]U-aminoallyl and m₂^7,3′OG[5′]pppp[5′]U-aminoallyl is reported. The final cap analog has been isolated with high purity (>99.8%) after ion-exchange column purification.     

Flavonoids and other compounds from Ouratea ferruginea (Ochnaceae) as anticancer and chemopreventive agents

The chemical study of the extracts from leaves and stems of Ouratea ferruginea allowed the identification of a new isoflavone, 5-hydroxy-7,3'4'5'-tetramethoxyisoflavone, and twenty two known compounds, including friedelin, 3β-friedelinol, lupeone, a mixture of sitosterol, stigmasterol and campesterol, sitosteryl- and stigmasteryl-3-O-b-D-glucopyranosides, 5,4'-dihydroxy-7,5',3'-trimethoxyisoflavone, 5,4'-dihydroxy-7,3'-di-methoxyisoflavone (7,3'-di-O-methylorobol), 5,7,4'-trihydroxy-3',5'-dimethoxyisoflavone (piscigenin), 2R,3R-epicatechin, syringic acid, 2,6-dimethoxybenzoquinone, 2,6-dimethoxyhydroquinone, syringic and ferulic aldehyde, a mixture of vanillic acid, 1-hydroxy-2-methoxy-4-(1E-3-hydroxy-1-propenyl)-benzene and 3,5-dimethoxy-4-hydroxy-dihydrocinamaldehyde, besides amenthoflavone and 7-O-methylamenthoflavone (sequoiaflavone) which are considered as chemotaxonomic markers of Ouratea. The structures were identified by IR, (1)H- and (13)C-NMR and GC-MS, HPLC-MS, besides comparison with literature data. The inhibitory effects of 5,4'-dihydroxy-7,5',3'-trimethoxyisoflavone, 7,3'-di-O-methylorobol, piscigenin and 7-O-methylamenthoflavone on cytochrome P450-dependent 7-ethoxycoumarin O-deethylase (ECOD) and glutathione S-transferase (GST) were evaluated in vitro. The 5,4'-dihydroxy-7,5',3'-trimethoxy-isoflavone was the best inhibitor, inhibiting almost 75% of GST activity. Sequoiaflavone was the most potent inhibitor, inhibiting ECOD assay in 75%. These activities allow us to consider both these flavonoids as potential anticancer and chemopreventive agents.     

One-pot four-component domino reaction for the synthesis of bifunctionalized spiro[indazolo[3,2-b]quinazoline-7,3′-indoline hybrids: A green approach

An efficient tandem route to obtain novel spiro[indazolo[3,2-b]quinazoline-7,3′-indolines has been explored. The one-step domino reaction proceeds via in situ generation of the 1H-indazol-3-amines followed by its reaction with the cyclic 1,3-dicarbonyls and isatin derivatives to furnish complex N-fused spiro-polyheterocyclic frameworks. This protocol describes a valuable route to concisely and feasibly obtain spiro[indazolo[3,2-b]quinazoline-7,3′-indolines from isatin derivatives. The present protocol is particularly attractive because of the following features: group-assisted-purification (GAP) chemistry process, low-cost solvent, convenience of operation, excellent atom economy, and high yields.     

Rapid access to the synthesis of polysubstituted δ-lactones via tandem stereoselective conjugate addition/α-alkylation of unsaturated 7,3-lactone-α-d-xylofuranose derivative

α-d-xylo-7,3-Unsaturated lactone, a versatile chiral building block, undergoes Cu-catalyzed conjugated addition with high yield and stereoselectivity. When the conjugated reaction is quenched with a suitable alkyl halide, a tandem stereoselective conjugated/α-alkylation reaction is achieved. Further, selective hydrolysis of the 1,2-O-isopropylidene moiety followed by oxidative cleavage and reduction reaction, afforded the title compounds.     

Fast chromatographic separation for the quantitation of the main flavone dyes in Reseda luteola (weld)

In the past decades, there has been a renewed interest in the use of natural dye plants for textile dyeing, e.g. Reseda luteola (weld). Its main yellow dye constituents are the flavones luteolin-7,3'-O-diglucoside, luteolin-7-O-glucoside and luteolin. The aim of this work was to develop a simple validated industrially usable quantitative method to assess the flavone content of R. luteola samples. The flavones were overnight extracted from the dried and ground aerial parts of the plant at room temperature via maceration with methanol-water 8:2. Afterwards, they were quantified through internal standardisation against chrysin by RP-HPLC-UV at 345 nm. The efficiency of the one-step extraction was 95%. The limits of detection (LOD) and quantitation (LOQ) were ≤ 1 ng and ≤ 3 ng, respectively, providing ample sensitivity for the purpose. The precision expressed as relative standard deviation of the entire method was <6.5% for the combined content of luteolin-7,3'-O-diglucoside, luteolin-7-O-glucoside and luteolin. The average absolute recovery (accuracy) at three spiking levels was 102% (range: 98-107%) and the relative recovery ranged from 99 to 102%. The separation was initially carried out on a traditional 250 mm × 4.6 mm 5 μm HPLC column (80 min run time, 35.9 mL MeOH). It was then speeded up by the use of a 50 mm × 3.0mm 1.8 μm UHPLC column (5 min run time, 1.4 mL MeCN), while still using a conventional HPLC system. Whereas, the retention times on the UHPLC column were relatively less reproducible, cross-validation showed that the quantitation of luteolin-7,3'-O-diglucoside, luteolin-7-O-glucoside and luteolin was not statistically significantly different, with comparable precision. The method using the UHPLC column is more sensitive. The analytical method described meets the demand for a very small manpower input per sample and uses standard laboratory equipment. Usage of short UHPLC columns opens up interesting possibilities for modernising HPLC-based phytochemical analyses.     

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The K_d values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.     

The Synthesis of trans‐Flavan‐3‐ol Gallates by Regioselective Oxidative Etherification and Their Cytotoxicity Mediated by 67 LR

We report on a chiral pool approach for the synthesis of trans‐flavan‐3‐ol gallates from epichlorohydrin. The trans‐flavan‐3‐ol gallates were prepared by the cycloetherification of the phenol at the C2 benzylic position of 2‐acylozyl‐1,3‐diarylpropane during regioselective C?H oxidation. The 1,3‐diarylpropanes were prepared starting from epichlorohydrin by epoxide opening with A and B ring precursors, followed by acylation of the resultant alcohol with galloyl chloride. The availability of both the enantiomers of epichlorohydrin allowed the preparation of the corresponding enantiomer using the same procedure. The cytotoxicity of the compounds against U266 cells was tested, in which 5‐deoxy‐7,3′‐O‐dimethyl gallocatechin gallate exhibited cytotoxicity that was more than ten times stronger than natural (?)‐EGCG. In addition, the absolute configuration of the derivatives did not critically affect the biological activity.     

Reaction of π-deficient aromatic heterocycles with ammonium polyhalides III. Halogenation of phenothiazin-5-oxide with benzyltriethylammonium polyhalides

Summary Halogenation of phenothiazin-5-oxide with benzyltriethylammonium polyhalides (BTEA) under mild conditions afforded chloro- and bromophenothiazines as well as a few unexpected products e.g. 1,3,7,9-tetrachloro-phenothiazin-5-oxide, 7,3-dibromo-3, 10-diphenothiazinyl tribromide, and 7,3-dichloro-3,10-diphenothiazinyl tetrachloroiodate. A new charge-transfer complex of phenothiazine-5-oxide with bromine is reported.

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Reaktion elektronenarmer aromatischer Heterocyclen mit Ammoniumpolyhalogenverbindungen, 3. Mitt. Halogenierung von Phenothiazin-5-oxid mit Benzyltriethylammoniumpolyhalogeniden

Zusammenfassung Halogenierung von Phenothiazin-5-oxid mit Benzyltriethylammoniumhalogeniden (BTEA) unter milden Bedingungen ergab neben Chlor- und Bromphenothiazinen einige unerwartete Reaktionsprodukte wir z.B. 1,3,7,9-Tetrachlorphenothiazin-5-oxid, 7,3-Dibrom-3,10-diphenothiazinylbromid und 7,3-Dichlor-3,10-diphenothiazinyltetrachloriodat. Außerdem wird über einencharge-transfer-Komplex von Phenothiazin-5-oxid mit Brom berichtet.