Mild, powerful, and robust methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively

We developed two efficient practical methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively. The present mild and robust reaction was performed by two separate methods both by combining cheap and readily available amines, N-methylimidazole, and N,N,N′,N′-tetramethylethylenediamine (TMEDA). Method A uses catalytic N-methylimidazole and TMEDA with an equimolar amount of K₂CO₃, whereas Method B uses equimolar amounts of N-methylimidazole and TMEDA. The salient features are as follows. (i) With regard to reactivity, Method B was superior to Method A for esterification and thioesterification, whereas cost-effective Method A was superior to Method B for amide formation. (ii) Amide formation proceeded smoothly between acid chlorides and less nucleophilic and stereocongested amines such as 2,6-dichloroaniline. (iii) This protocol was applied to the successful synthesis of two agrochemicals, bromobutide and carpropamid.     

Synthesis of sugar-derived isoselenocyanates, selenoureas, and selenazoles

Aryl, alkyl, and sugar-derived isoselenocyanates were prepared by a one-pot procedure starting from the corresponding formamides, using triphosgene as a dehydrating agent, triethylamine, and black selenium powder. The preparation of sugar selenoureas by coupling of O-protected sugar-derived isoselenocyanates with different amines, and by coupling of unprotected glycopyranosyl amines with phenyl isoselenocyanate was also accomplished. The synthesis of a glucopyranos-2-yl-selenazole starting from O-protected 2-amino-2-deoxy-d-glucose by coupling with benzoyl isoselenocyanate, Se-alkylation with phenacyl bromide, and acid-catalyzed dehydration is also reported. Unprotected N-(β-d-glucopyranosyl)-N′-phenylselenourea was transformed into a 1,2-trans-fused bicyclic isourea upon treatment with aqueous hydrogen peroxide; the same isourea was prepared by a one-pot three-step procedure from β-d-glycopyranosylamine by thiophosgenation, coupling with aniline, and HgO-mediated desulfurization.     

Total synthesis of N,O,O,O-tetraacetyl-d-ribo-phytosphingosine and its 2-epi-congener

Total synthesis of the natural d-ribo-phytosphingosine I and its 2-epimer III in the protected form was achieved through a common strategy. The aza-Claisen rearrangement of allylic thiocyanate (Z)-V incorporated the new stereogenic centre with nitrogen and the subsequent Wittig olefination constructed a non-polar side chain. Hydrogenation, followed by removal of protecting groups, completed the syntheses of I and III.     

Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil, 3,6-dimethyluracil,thymine, and quinazoline-2,4-dione moieties

A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with protected azido β-d-ribofuranose. The obtained compounds differ in both the nature of the pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the β-d-ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were evaluated for their cytotoxicity in vitro.     

Isolation,Characterization, Complete Structural Assignment,and Anticancer Activities of the Methoxylated Flavonoids from Rhamnus disperma Roots

Different chromatographic methods including reversed-phase HPLC led to the isolation and purification of three O-methylated flavonoids; 5,4’-dihydroxy-3,6,7-tri-O-methyl flavone (penduletin) (1), 5,3’-dihydroxy-3,6,7,4’,5’-penta-O-methyl flavone (2), and 5-hydroxy-3,6,7,3’,4’,5’-hexa-O-methyl flavone (3) from Rhamnus disperma roots. Additionlly, four flavonoid glycosides; kampferol 7-O-α-L-rhamnopyranoside (4), isorhamnetin-3-O-β-D-glucopyranoside (5), quercetin 7-O-α-L-rhamnopyranoside (6), and kampferol 3, 7-di-O-α-L-rhamnopyranoside (7) along with benzyl-O-β-D-glucopyranoside (8) were successfully isolated. Complete structure characterization of these compounds was assigned based on NMR spectroscopic data, MS analyses, and comparison with the literature. The O-methyl protons and carbons of the three O-methylated flavonoids (1–3) were unambiguously assigned based on 2D NMR data. The occurrence of compounds 1, 4, 5, and 8 in Rhamnus disperma is was reported here for the first time. Compound 3 was acetylated at 5-OH position to give 5-O-acetyl-3,6,7,3’,4’,5’-hexa-O-methyl flavone (9). Compound 1 exhibited the highest cytotoxic activity against MCF 7, A2780, and HT29 cancer cell lines with IC₅₀ values at 2.17 µM, 0.53 µM, and 2.16 µM, respectively, and was 2–9 folds more selective against tested cancer cell lines compared to the normal human fetal lung fibroblasts (MRC5). It also doubled MCF 7 apoptotic populations and caused G₁ cell cycle arrest. The acetylated compound 9 exhibited cytotoxic activity against MCF 7 and HT29 cancer cell lines with IC₅₀ values at 2.19 µM and 3.18 µM, respectively, and was 6–8 folds more cytotoxic to tested cancer cell lines compared to the MRC5 cells.     

Oxidizing O,O,O-trimethyl phosphorothioate with hydrogen peroxide or ozone

Oxidization of O,O,O-trimethyl phosphorothioate to the corresponding oxo (P=O) compound is accomplished under mild conditions with hydrogen peroxide or ozone. Urea hydroperoxide was found to be a serviceable solid-state source of hydrogen peroxide; it was a better oxidizing agent than 30% hydrogen peroxide and resulted in better yield. It was also proved that ozone was the most effective oxidizer, with formation of purer products in higher yield (90.1%) than with hydrogen peroxide.     

Variation in fat soluble vitamins (A,D, E,K) in in vitro and ex vitro germinated chickpea (Cicer arietinum L.) seedlings,as revealed by high performance liquid chromatography

In present communication, effect of in vitro and ex vitro culture conditions was investigated on the yield of fat soluble vitamins in chickpea (Cicer arietinum L.) seedlings analyzed by high performance liquid chromatography (HPLC). Amongst the tested culture conditions (in vitro and ex vitro); in vitro condition proved to be highly effective compared to ex vitro. We noticed a significant difference in vitamins D (ergocalciferol), E (α-tocopherol) and K (phylloquinone) yields in chickpea seedlings grown in two different conditions. Maximum yield with a linear increase in vitamins D and E was noticed upto 9 days old in vitro grown seedlings. Vitamin K yield was also high in in vitro grown seedlings with a linear increase upto 11 days. Although, vitamin A was not detected, the vitamin production in germinating seeds was, therefore, age and culture condition dependent. The study revealed that, in in vitro condition, the level of fat soluble vitamins enhanced in seedlings, which could be used for human consumption with value addition in the diet of vegetarians.     

Phytochemical Profile,Antimicrobial, Cytotoxic,and Antioxidant Activities of Fresh and Air-Dried Satureja nabateorum Essential Oils

Satureja nabateorum (Danin and Hedge) Bräuchler is a perennial herb in the Lamiaceae family that was discovered and classified in 1998. This green herb is restricted to the mountains overlooking the Dead Sea, specifically in Jordan’s southwest, the Edom mountains, and the Tubas mountains in Palestine. Gas chromatography-mass spectrometry (GC-MS) analysis of essential oil (EO) of air-dried and fresh S. nabateorum resulted in the identification of 30 and 42 phytochemicals accounting for 99.56 and 98.64% of the EO, respectively. Thymol (46.07 ± 1.1 and 40.64 ± 1.21%) was the major compound, followed by its biosynthetic precursors γ-terpinene (21.15 ± 1.05% and 20.65 ± 1.12%), and p-cymene (15.02 ± 1.02% and 11.51 ± 0.97%), respectively. Microdilution assay was used to evaluate the antimicrobial property of EOs against Staphylococcus aureus (ATCC 25923), clinical isolate Methicillin-Resistant Staphylococcus aureus (MRSA), Enterococcus faecium (ATCC 700221) Klebsiella pneumoniae (ATCC 13883), Proteus vulgaris (ATCC 700221), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853) and Candida albicans (ATCC-90028). With a MIC of 0.135 μg/mL, the EOs has the most potent antibacterial action against K. pneumonia. Both EOs display good antifungal efficacy against C. albicans, with a MIC value of 0.75 μg/mL, which was better than that of Fluconazole’s (positive control, MIC = 1.56 μg/mL). The antioxidant capacity of EOs extracted from air-dried and fresh S. nabateorum was determined using the DPPH assay, with IC₅₀ values of 4.78 ± 0.41 and 5.37 ± 0.40 μg/mL, respectively. The tested EOs showed significant cytotoxicity against Hela, HepG2, and COLO-205 cells, with IC₅₀ values ranging from 82 ± 0.98 to 256 ± 1.95 μg/mL. The current work shows there is a possibility to use the S. nabateorum EOs for various applications.     

Synthesis of (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol,the aggregation pheromone of the ambrosia beetle Platypus quercivorus,its racemate, (1R,4R)- and (1S,4S)-isomers

(S)-Perillyl alcohol was converted to (R)-cryptone (91.5–93% ee) in six steps, which was then treated with methyllithium to give (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol, the aggregation pheromone of the ambrosia beetle Platypus quercivorus. The racemic pheromone was also prepared by methylation of (±)-cryptone. Both (1R,4R)- and (1S,4S)-isomers (98% ee) of the pheromone were synthesized from the enantiomers of dihydrolimonene oxide.     

Salt, concentration, and temperature effects on an asparagine-based, aqueous Diels-Alder cycloaddition

Results are reported on the salt, concentration, and temperature effects in an aqueous, auxiliary-mediated asymmetric Diels-Alder cycloaddition. The auxiliaries were prepared under basic aqueous conditions from asparagine and trimethylacetaldehyde, and coupled to acryloyl chloride to generate dienophiles in one pot. Temperature and concentration modestly impacted cycloaddition stereochemistry. Experiments with a range of salts examined the speculation that complexation between the counterion of the auxiliary carboxylate and the dienophile carbonyl promotes the formation of the minor endo product, reducing cycloaddition diastereoselectivity for the endo products. The transformation was poorly selective for the carboxylic acid but gave moderate selectivities for several metallated carboxylates. The magnitude of the diastereoselectivity of the endo products was weakly dependent on carboxylate counterion and more strongly influenced by the basicity of the salt anion. Data presented suggest that Lewis acid catalysis reduces cycloaddition diastereoselectivity for the endo products.     

Synthesis,Formulation, and Adjuvanticity of Monodesmosidic Saponins with Olenanolic Acid,Hederagenin and Gypsogenin Aglycones,and some C‐28 Ester Derivatives

In an attempt to discover a new synthetic vaccine adjuvant, the glycosylation of hederagenin, gypsogenin, and oleanolic acid acceptors with di‐ and trisaccharide donors to generate a range of mimics of natural product QS‐21 was carried out. The saponins were formulated with phosphatidylcholine and cholesterol, and the structures analyzed by transmission electron microscopy. 3‐O‐(Manp(1→3)Glcp)hederagenin was found to produce numerous ring‐like micelles when formulated, while C‐28 choline ester derivatives preferred self‐assembly and did not interact with the liposomes. When alone and in the presence of cholesterol and phospholipid, the choline ester derivatives produced nanocrystalline rods or helical micelles. The effects of modifying sugar stereochemistry and the aglycone on the immunostimulatory effects of the saponins was then evaluated using the activation markers MHC class II and CD86 in murine bone marrow dendritic cells. The most active saponin, 3‐O‐(Manp(1→3)Glcp)hederagenin, was stimulatory at high concentrations in cell culture, but this did not translate to strong responses in vivo.     

Near-infrared spectroscopic measurements of volume expansion and composition of CO2-expanded ethyl acetate,acetone, tetrahydrofuran,acetonitrile, methanol-OD,and dimethyl sulfoxide

CO₂-expanded liquid (CXL) is a mixture of organic solvent with high-pressure CO₂ whose volume is increased by CO₂ dissolved in it. CXLs have attracted attention as tunable solvents, because the solvent properties can be widely controlled by the pressure. The volume expansion and the solubility of CO₂ were measured by near-infrared spectroscopy for 6 CXLs at various pressures up to 55 bar and 40 °C. The molarity of organic solvent was determined from the absorbance of the 3ν and 2ν + δ bands, and that of CO₂ was obtained from the area of the 3ν₃ band, whose peak shifted to higher frequency with increasing pressure due to a decrease in the molecular interaction around CO₂. The expansion coefficient was shown to be an increasing function of the pressure with larger slope at higher pressure, and the mole fraction of CO₂ in the liquid phase was an almost linearly increasing function of the pressure. The results were in quantitative agreement with the literature data measured by conventional sampling method, indicating the validity of the spectroscopic method.     

Solid-phase synthesis of quinoxaline, thiazine, and oxazine analogs through a benzyne intermediate

A solid-phase synthetic route to quinoxaline, thiazine, and oxazine analogs is described. N-Alloc-3-amino-3-(2,4-difluoro-5-nitrophenyl)propanoic acid was tethered to Rink resin via its carboxylic acid group. The 4-arylfluorine was displaced with a primary amine, alcohol, or thiol to create, respectively, a resin bound aniline, phenol, or thiophenol derivative with one diversity element and one single atom (e.g., N, S, or O) diversity point. A fused heterocyclic system was subsequently created via a benzyne heterocyclization initiated by dehydrofluorination with strong base. Acid treatment released the desired products in high yield and moderate purity.     

Microwave spectrum,structure, dipole moment and internal rotation of ethyl fluorosilane

Microwave spectra of the trans and gauche isomers of ethyl fluorosilane and their eleven isotopically substituted species have been measured. The r_s structures of the two isomers were determined from the observed moments of inertia. The molecular structures found for the two isomers in the present study are compared with those of analogous molecules. Dipole moments of the two isomers were determined by Stark-effect measurements and are also compared with those of analogous molecules. The energy difference between the trans and gauche isomers was obtained from the relative intensity measurements of the spectra and the barrier to internal rotation of the methyl group for the gauche isomer was obtained from the A—E splittings of the spectra in the first excited methyl torsional state. The V₃ value was 2775 ± 25 cal mol^?1.     

Polyparaxylylene-CdS nanocomposite films: Optical spectra, photoluminescence, and surface topography

For polyparaxylylene-CdS nanocomposite films prepared by solid-phase cryochemical synthesis, the dependences of the optical absorption spectra, photoluminescence intensity, and surface topography on the CdS concentration were examined. It was revealed that the most significant changes, such as the shift of the position of the exciton absorption band by ～1 eV and the increase of the surface roughness (the magnitude of variation of heights h _max ? h _min along a surface profile) occur within a CdS concentration range of from ～5 to ～8 vol %. The average size of the nanoparticles was determined from the position of the exciton absorption maximum: 2R _np ? ? 3 nm at c ≤ 5 vol % and 2R _np ≥ 5?7 nm at c ≥ 10 vol %. The formation of 3-nm particles at low CdS concentrations was confirmed by the existence of exciton photoluminescence with maximum at 370 nm. Exciton luminescence was not observed at c ≥ 10 vol %. By contrast, at all c values, photoluminescence with maxima at ～520 and ～570 nm, which is usually assigned to interstitial S and Cd atoms, correspondingly, and a the weak emission of unknown nature with a maximum at 545 nm were observed.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Synthesis, structure, and properties of pyrazole-4-carbaldehyde oximes

1-Alkyl-1H-pyrazole-4-carbaldehyde oximes reacted with acetic anhydride to give the corresponding nitriles, which is typical for anti isomers of aldoximes. The anti configuration of 5-methyl-1-propyl-1H-pyrazole-4-carbaldehyde oxime in crystal was unambiguously determined by X-ray analysis.     

Synthesis, structural aspects and cytotoxicity of the natural cyclopeptides yunnanins A, C and phakellistatins 1, 10

Yunnanins A and C, two cyclic heptapeptides occurring in the roots of Stellaria yunnanensis, and phakellistatins 1 and 10, a hepta- and an octacyclopeptide first isolated from marine sponges of the genus Phakellia, were efficiently synthesized using a combination of solid and solution-phase techniques. Structural analysis on the synthetic members of the yunnanin series showed that the synthetic sample of yunnanin A exhibited a configurational pattern at the Pro peptide linkages identical to the natural product (trans-Pro³, trans-Pro⁵), while yunnanin C was obtained as a complex mixture of geometric/conformational isomers; the major isomer (trans-Pro³) was indistinguishable from the natural cyclopeptide and co-occurred along with lower amounts of a mixture (1:1 ratio) of two different rotamers, both displaying cis geometry at the Pro³ linkage. In the phakellistatin series, the synthetic phakellistatin 1 (determined as cis-Pro¹, cis-Pro³, cis-Pro⁵) was identical to the natural one, while two different isomeric products of phakellistatin 10 could be obtained: a major one (trans-Pro¹, trans-Pro⁴, trans-Pro⁶) showing spectral properties superimposable with the natural metabolite, and a minor geometric isomer of the natural cyclopeptide. Interestingly, the synthetic cyclopeptides, although found to be chemically identical with their natural counterparts, did not display the same biological properties (in vitro cytotoxicity against a panel of cancer cell lines), leaving presently open the question whether or not the potent bioactivity reported in the literature should really be attributed to these natural cyclic peptides.     

A Validated, Stability-Indicating, LC Method for Rabeprazole Sodium

We present a simple and reliable method for simultaneous determination of voriconazole and its main metabolite resulting from N-oxidation (UK-121,265), in human plasma. The work-up procedure used acetonitrile and potassium salts to precipitate plasma proteins. No internal standard was used. The chromatographic system used a LiChroCART^® 250-4 cartridge packed with LiChrospher^® 100 RP-8 (diameter particules, 5 μm). The UV monochromatic detector was set on 260 nm. The mobile phase consisted of a 60/40 (v/v) mixture of acetonitrile and water. The flow rate was 1 mL min^?1. The retention times for voriconazole and its metabolite were 8.98 and 4.02 min respectively, and total run time was 12 min. The linearity of the method was investigated from 0.31 to 10.0 mg L^?1; the lowest limit of quantification was 0.30 mg L^?1. Precision ranged from 2.41% to 6.32% for voriconazole and 0.80% to 11.6% for the N-oxide voriconazole metabolite. Accuracy was between 93.0% and 101% for voriconazole and 90.0% and 101% for the N-oxide voriconazole metabolite. This rapid and accurate method could be interesting to investigate metabolite/voriconazole ratio with respect to CYP2C19 genetic status and CYP3A4 activity changes.     

Synthesis of Amaryllidaceae alkaloids, siculine, oxocrinine, epicrinine, and buflavine

Three crinane type of alkaloids isolated from Amaryllidaceae family were synthesized by taking advantage of the PIFA-mediated intramolecular p-p′ diphenol coupling reaction of norbelladine derivatives. Furthermore, buflavine was also prepared by using the p-p′ diphenol coupling followed by dienone-phenol rearrangement as a key step.