Estrogenic and anti-estrogenic activities of Cassia tora phenolic constituents

Through an estrogenic activity bioassay-guided fractionation of the 70% ethanolic extract of Cassia tora seeds two new phenolic triglucosides, torachrysone 8-O-[beta-D-glucopyranosyl(1-->3)-O-beta-D-glucopyranosyl(1-->6)-O-beta-D-glucopyranoside] (1) and toralactone 9-O-[beta-D-glucopyranosyl-(1-->3)-O-beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranoside] (2), along with seven known compounds were isolated. The structures of the new compounds were elucidated on the basis of spectroscopic and chemical evidence. The estrogenic activity of the fractions and the isolated compounds were investigated using the estrogen-dependent proliferation of MCF-7 cells. In addition, the yeast two hybrid assay expressing estrogen receptor alpha (ERalpha) and beta (ERbeta) and the ERalpha competitor screening assay (ligand binding screen) were used to verify the binding affinities of the isolated compounds to ER. Furthermore, a naringinase pre-treatment of the 70% alcoholic extract of Cassia tora seeds resulted in a significant increase in its estrogenic activity. From the naringinase pre-treated extract six compounds were isolated, among which 6-hydroxymusizin and aurantio-obtusin showed the most potent estrogenic activity, while torachrysone, rubrofusarin and toralactone showed a significant anti-estrogenic activity. Finally, the structure requirements responsible for the estrogenic activity of the isolated compounds were studied by investigating the activity of several synthetic compounds and chemically modifying the isolated compounds. The basic nucleus 1,3,8-trihyroxynaphthalene (T(3)HN) was found to play a principal role in the binding affinity of these compounds to ER.     

Application of bis(iminophosphorane) in heterocyclic synthesis: new entries to symmetrically or unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones

The bis(carbodiimides) 4, obtained from bis-aza-Wittig reactions of bis(iminophosphorane) 3 with 2 equiv of aromatic isocyanates, were reacted with secondary amine to give symmetrically substituted 2,7-diaminothieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-dione 6 in the presence of a catalytic amount of EtO(-)Na(+). Reactions of 4 with phenols or ROH in the presence of a catalytic amount of potassium carbonate or RO(-)Na(+) gave symmetrically substituted 2,7-diaryl(alkyl)oxythieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 6 in satisfactory yields. However, iminophosphoranes 9 were obtained via reaction of bis(iminophosphorane) 3 with 1 equiv of aromatic isocyanate and subsequent reaction with an amine in the presence of a catalytic amount of EtO(-)Na(+). Further reaction of iminophosphoranes 9 with aromatic isocyanates and various nucleophile generated unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 12 in good yields.     

Development of 1,3a,6a-triazapentalene-labeled enterobactin as a fluorescence quenching sensor of iron ion

1,3a,6a-Triazapentalene (TAP)-labeled enterobactin was developed as an iron ion sensor. 3-Acetylated-TAP was successfully introduced to the catechol ring of enterobactin, a well-recognized siderophore secreted by various Gram-negative bacteria. The fluorescence of TAP-labeled enterobactin decreased gradually as the amount of Fe³⁺ ion as an additive was increased, and 1.2 equiv of Fe³⁺ ion completely quenched the fluorescence. In clear contrast, when other metal ions were used, the fluorescence of TAP-labeled enterobactin remained even at 5.0 equiv.     

Highly enantioselective aza Morita-Baylis-Hillman reaction catalyzed by bifunctional beta-isocupreidine derivatives

The aza-MBH reaction of imines 1 and beta-naphthyl acrylate 2 in the presence of C-6' modified beta-isocupreidine derivative 1c (0.1 equiv) and beta-naphthol 5 (0.1 equiv) afforded the corresponding (3S)-aza-MBH adducts 4 in high yield and excellent enantiomeric excess. These catalytic conditions allowed the aliphatic imines to be employed for the first time as electrophilic partners of the aza-MBH reaction. The coexistence of two H-bond donors with different acidic strengths was found to be crucial for the observed high enantioselectivity.     

Highly atom economical uncatalysed and I2-catalysed silylation of phenols,alcohols and carbohydrates,using HMDS under solvent-free reaction conditions (SFRC)

An uncatalysed silylation of phenols, regardless on the aggregate state and nature of the substituents with 0.55 equiv of HMDS under solvent-free reaction conditions (SFRC) at room temperature is reported. Sterically hindered phenols, carbohydrates and most of the alcohols additionally required a catalytic amount (up to 2 mol %) of iodine. The reaction protocol is very simple; obtaining a pure product, particularly of uncatalysed reactions, was frequently a completely solvent-free process.     

Investigation of the stability of thiosialosides toward hydrolysis by sialidases using NMR spectroscopy

[formula: see text] 1H NMR spectroscopy has been used to investigate whether the alpha(2-->6)-linked thiosialoside 3 and the alpha(2-->3)-linked thiosialoside 9 are hydrolyzed in the presence of Vibrio cholerae sialidase. Similarly, the hydrolysis of the O-ketosides Neu5Ac-2-O-alpha-(2-->3)-Gal beta Me (4) and the alpha-(2-->6)-sialyllactoside 7, representing natural alpha(2-->3)- and alpha(2-->6)-linked sialosides, respectively, was investigated. The results of the 1H NMR experiments clearly demonstrate that the thiosialosides are not hydrolyzed by Vibrio cholerae sialidase. As expected, the O-sialosides are hydrolyzed to give N-acetyl-alpha-D-neuraminic acid as the first product of substrate cleavage.     

Nickel(II) chloride hexahydrate catalyzed reaction of aromatic aldehydes with 2-mercaptoethanol: formation of supramolecular helical assemblage of the product

Various aromatic aldehydes on reaction with 2-mercaptoethanol provided an unanticipated product, bis(2-hydroxyethyl)dithioacetals (3) as the major product along with the expected product 1,3-oxathiolanes (4) in the presence of 0.05 equiv amount of nickel(II) chloride hexahydrate (NiCl₂·6H₂O) under solvent-free conditions. Products 3c and 3e exhibit an interesting hydrogen-bonded infinite supra-molecular helical structure.     

Detection and confirmation of saxitoxin analogues in freshwater benthic Lyngbya wollei algae collected in the St. Lawrence River (Canada) by liquid chromatography–tandem mass spectrometry

The presence of cyanotoxins in benthic Lyngbya wollei algae samples collected in a fluvial lake along the St. Lawrence River, Canada, was investigated using a multi-toxins method. Hydrophilic interaction liquid chromatography (HILIC) and reverse phased liquid chromatography (RPLC) were coupled to triple quadrupole mass spectrometry (LC-QqQMS) for quantification and to quadrupole-time of flight mass spectrometry (LC-QqTOFMS) for screening and confirmation. The presence of two saxitoxin analogues, LWTX-1 and LWTX-6, was confirmed in benthic Lyngbya wollei algae samples. Concentration of LWTX-1 was between 209 ± 5 and 279 ± 9 μg g^?1. No other targeted cyanotoxin (such as anatoxin-a, nodularin, microcystin-LR, microcystins-RR and saxitoxin) was found in the samples. The presence of LWTX-6 was observed by using a screening approach based on an in-house database of cyanotoxins, an algorithm of identification and high resolution mass spectrometry measurements on the precursor and product ions. This work demonstrates the need for more research on the fate of benthic cyanotoxins in aquatic ecosystems such the St. Lawrence River.     

Enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines catalyzed by β-aminoalcohols with the prolinol skeleton

Several β-aminoalcohols with the prolinol framework are shown to be very efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of the catalyst leads to the expected addition products in good yields and with ee up to 94% in a reaction time of only 4 h at room temperature. This ee is the highest value reported so far using 0.5 equiv of an aminoalcohol as a promoter. High enantioselectivities are obtained in the addition of dialkylzincs to both aromatic and aliphatic imines. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. A very interesting effect of the addition rate and temperature on the enantioselectivity was also observed.     

A convenient method for the kinetic resolution of racemic 2-hydroxyalkanoates using diphenylacetic anhydride (DPHAA) and a chiral acyl-transfer catalyst

Diphenylacetic anhydride (DPHAA) was found to be a useful reagent for the kinetic resolution of racemic 2-hydroxyalkanoates in the presence of a catalytic amount of (R)-benzotetramisole ((R)-BTM). The combined use of DPHAA and (R)-BTM effectively produced a variety of the optically active 2-hydroxyalkanoates and the corresponding 2-acyloxyalkanoates from racemic 2-hydroxyalkanoates (s-values = 42–177). A fairly broad substrate scope was demonstrated by this novel chiral induction system. We also revealed that the use of only 0.3 equiv of DPHAA is enough to provide the optically active 2-acyloxyalkanoates in good yields and with excellent ee’s by the added use of 0.3 equiv of pivalic anhydride for the kinetic resolution of the racemic 2-hydroxyalkanoates.     

An efficient microwave assisted synthesis of N′-aryl/(alkyl)-substituted N-(4-hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and limitations

Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in isopropyl alcohol for only 10 min at 110–120 °C under microwave conditions gave the corresponding N′-alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields were greatest when >1.0 equiv. of amines were employed, but excellent results were also obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0 equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron withdrawing substituents (e.g. CO₂H) or pi-deficient heterocycles (e.g. variously substituted aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino acids did not give detectable products. Work-up was exceedingly simple, and involved simple collection and washing of product on a sintered glass funnel. Products were obtained in analytically pure form and required approximately 1 h to prepare, start to finish.     

N-Benzyl-l-prolinol: an efficient catalyst for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines

Commercially available N-benzyl-l-prolinol has shown to be a very efficient catalyst for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of this β-aminoalcohol as a catalyst leads to the expected addition products in good yields and with ees up to 92% in a reaction time of only 4 h at room temperature. This ee is almost equal to the highest value reported so far using 0.5 equiv of an aminoalcohol as promoter, although the reaction time is much shorter in our case. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. An interesting effect of the addition rate and temperature on the enantioselectivity has been observed.     

含呋喃共轭桥有机非线性光学生色团的合成及性能研究

通过两次羟醛缩合反应合成了一种含呋喃共轭桥的有机非线性光学生色团分子2-二氰亚甲基-3-氰基-4-[2-(4-二乙氨基-苯乙烯基-呋喃基-5)-乙烯基]-5,5-二甲基-2,5-二氢呋喃(EFFC), 用IR谱、¹H NMR谱以及元素分析表征确认了其结构. 热失重分析表明, 材料的热分解温度T_d为250℃. 用密度泛函理论的B3LYP方法在6-31G基组下对这种生色团分子进行了结构优化, 并在相同基组下对分子的静态二阶极化率进行了计算, 分子的b₀=6.5×10^-28 esu. 将分子以18%的质量比与聚砜进行主-客体掺杂, 用溶胶凝胶法制备成膜后进行极化, 用二次谐波法对掺杂极化聚合物薄膜的电光系数进行测量, 其r₃₃值最高达到80 pm/V.     

A new umpolung for direct γ-regioselective nucleophilic addition of alcohols to γ-enolizable α,β-unsaturated aldehydes

A direct γ-regioselective nucleophilic addition of alcohols toward γ-enolizable α,β-unsaturated aldehydes was developed using a catalytic amount of MeSO₃H (30 mol%) and a stoichiometric amount of chloranil (1.0 equiv) as the oxidant. The addition of hexafluoroisopropanol (HFIP) was found to accelerate this cross-dehydrogenative coupling, furnishing diverse alcoholic adducts with high γ-regio- and E-stereoselectivities.     

Ammonium chloride promoted Ugi four-component, five-center reaction of alpha-substituted alpha-isocyano acetic acid: a strong solvent effect

[reaction: see text] Conditions have been developed for the multicomponent synthesis of di- and tetrapeptide (7) based on the unique reactivity of alpha-isocyano acetic acid (4 and its alpha-substituted derivatives) by an Ugi four-component, five-center reaction. Simply mixing 4, a carbonyl compound (aldehyde or ketone, 8), and a secondary amine (9) (ratio: 1:1:2) in toluene in the presence of 1.5 equiv of ammonium chloride afforded the desired product in good to excellent yield as a mixture of two diastereomers.     

Catalytic enantioselective protonation of lithium enolates with chiral imides

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton sources examined in the protonation of the lithium enolate of 2,2,6-trimethylcyclohexanone catalyzed by (S,S)-imide 1, 2, 6-di-tert-butyl-p-cresol (BHT) and its derivatives gave the highest enantiomeric excess. For example, 90% ee of (R)-enriched ketone was obtained when (S,S)-imide 1 (0.1 equiv) and BHT (1 equiv) were used. Use of 0.01 equiv of the chiral catalyst still caused a high level of asymmetric induction. For catalytic protonation of the lithium enolate of 2-methylcyclohexanone, chiral imide 6 possessing a chiral amide portion was superior to (S,S)-imide 1 as a chiral proton source and the enolate was effectively protonated with up to 82% ee.     

Design and electrochemical characterization of a new cobalt(II)–cyclodextrin complex. Evidence for a supramolecular stabilization of the Co(I) state

The electrochemical behavior of a new cobalt–cyclodextrin (CD) complex was investigated, in dimethylformamide, from CoX₂ (X = Br and BF₄) in the presence of 1 equiv. 6-Deoxy-6-N-(2-methyliminopyridine)-β-cyclodextrin as ligand. Under these conditions, it was demonstrated for the first time, that the electrogenerated cobalt(I) species can be kinetically and thermodynamically stabilized. The electrochemical study of CoX₂ in the presence of a related iminopyridine ligand (2-pyridyl-N-benzylmethylimine), in which the cyclodextrin (CD) group was replaced by a simple aryl moiety, allowed to highlight the crucial role of the CD in this unexpected stabilization. Importantly, this unprecedented result was only observed when both the iminepyridine and the CD moieties were together covalently attached. Importantly, the supramolecular stabilized low-valent cobalt species remained fairly reactive towards aromatic halides despite its intrinsic stability. This original work opens new opportunities for the development of more selective catalytic processes both in organic and aqueous media.     

Syntheses of Chiral Phosphazenes with Stereogenic Centers: NMR Behavior in the Presence of a Chiral Solvating Agent

The condensation reactions of tetrachloro mono ( 1 and 2 ) and bisferrocenyl spirocyclotriphosphazenes ( 3 – 5 ) with morpholine in tetrahydrofuran gave the partly morpholino‐substituted ferrocenylphosphazenes. When the reactions were carried out with equal amounts of 1 – 5 and morpholine, the mono‐substituted ferrocenylphosphazenes ( 1a, 3a–5a ) formed as the major product. While the reactions were made with 1 equiv of 1–5 and 2 equiv of morpholine, the corresponding geminal–phosphazenes ( 1b–5b ) were isolated. In addition, the condensation reactions of 1 equiv of 1–5 and 3 equiv of morpholine resulted in the formation of di‐( 1b–5b ), tri‐( 2c–5c ), and tetra‐substituted phosphazenes. The tri‐substituted compounds were isolated as major products. Some new phosphazenes have stereogenic P center(s). The stereogenic properties of 1a and 2c were investigated using ³¹P nuclear magnetic resonance (NMR) spectroscopy in the presence of the chiral solvating agent; (S)‐(+)‐2,2,2‐trifluoro‐1‐(9′‐anthryl)ethanol. The structures of all the phosphazenes were characterized by one‐dimensional ¹H, ¹³C, and ³¹P NMR, and two‐dimensional heteronuclear single quantum coherence spectral data. The salient spectral properties of the phosphazenes were presented.     

Effect of acid catalysis on the direct electrophilic fluorination of ketones,ketals, and enamides using Selectfluor™

The fluorination of ketones, ketals, and enamides has been achieved using the electrophilic fluorinating reagent Selectfluor? (F-TEDA-BF₄). For the reactions of ketones and ketals the use of sulfuric acid (0.1 equiv) as an additive was found to facilitate the reaction leading to more rapid product formation. This behavior is analogous to the known effects of acid catalysis on the bromination of ketones. The reactions were generally quite selective leading to the formation of monofluorinated products, and could be accomplished on reaction scales up to 85 mmol using N-protected piperidone based substrates. Reactions in the presence of MeOH led to the formation of the corresponding fluoroketones or fluoroketals depending upon the substrate. The formation of the fluoroketals in this manner, as well as the fluorination of cyclic enamides are examples of multi-component coupling reactions.     

Unusual reactivity of a disilyne with 4-dimethylaminopyridine: formation of an intramolecularly N-coordinated silylene and its isomerization to a zwitterionic silyl anion

Reaction of isolable 1,1,4,4-tetrakis[bis(trimethylsilyl)methyl]-1,4-diisopropyltetrasila-2-yne (1) with an equiv amount of 4-dimethylaminopyridine unexpectedly produced the intramolecularly N-coordinated silylene 2 as the primary product. However, 2 was not thermally stable at room temperature in solution and slowly isomerized to silyl anion 3 with a zwitterionic structure via 1,2-hydrogen migration followed by Si-N bond formation.