Synthesis of new chiral pincer-complex catalysts for asymmetric allylation of sulfonimines

Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties with iodoresorcinol followed by oxidative addition of palladium(0). The X-ray analysis of complex 5a revealed that the BINOL rings form a well-defined chiral pocket around the palladium atom. This chiral environment can be further modified by γ-substitution of the BINOL rings. Preliminary studies for electrophilic allylation of sulfonimine 2 with allylstannane revealed that the presented chiral complexes are promising asymmetric catalysts for preparation of chiral homoallyl amines. The best result was achieved employing catalytic amounts of γ-Me BINOL complex 6 affording homoallyl amine 4 with 59% ee and 74% isolated yield.     

Asymmetric catalysis 87. Enantioselective allylation of 1,5-dimethylbarbituric acid with Pd catalysts and new optically active PN ligands

The new PN ligands 5, 6 and 7 were prepared by Schiff base condensation of 2-formylphenyl(diphenyl)phosphine (1) with the optically active amines (R)-(−)-2-aminobutanol (2), (S)-(+)-2-aminobutanol (3) and (1S,2S)-2-amino- 1-phenyl-1,3-propanediol (4). These new ligands were used in the Pd catalysed allylation of 1,5-dimethylbarbituric acid with allylacetate. 5-Allyl-1,5-dimethylbarbituric acid was obtained with an optical induction of up to 12.7% ee.     

A novel synthesis of acyclonucleosides via allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one

The allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (1) gave, in addition to the anticipated 1-N-allyl derivative (2), a dehydrative cyclized product, 1-N-allyl-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxalin-2-one (4) and its isomeric O-allyl derivative 3. The O-allyl group in 3 underwent acetolysis under acetylation conditions, in addition to the acetylation of the hydroxyl group, to afford 2-acetoxy-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline (8) instead of the O-acetyl derivative of 3. Allylation of the tri-O-acetyl derivative of 1 caused the elimination of a molecule of acetic acid in addition to N-allylation to give 1-N-allyl-3-[3,4-di-O-acetyl-2-deoxy-1-(phenylhydrazono)but-2-en-1-yl]quinoxalin-2-one (11). Hydroxylation of the allyl group gave a glycerol-1-yl acyclonucleoside which can be alternatively obtained by a displacement reaction of the tosyloxy group in 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)glycerol (14), followed by deisopropylidenation. 1-N-(2,3-Dibromopropyl)-3-[5-(hydroxymethyl)-1-(4-bromophenyl)pyrazol-3-yl]quinoxalin-2-one (15) underwent azidolysis to give a 2,3-diazido derivative. The assigned structures were based on spectral analysis. The activity of compounds 2, 4, 6, and 15 against hepatitis B virus was studied.     

Synthesis of pheromones by stereoselective carbonyl olefination: A unitised construction principle

A route of synthesis for the preparation of unsaturated pheromones is presented. It permits the synthesis of monounsaturated and diunsaturated compounds, with varying position and configuration of double bonds, by stereoselective carbonyl olefination. The choice of appropriate ω-functional aldehydes and phosphoranes makes possible the synthesis of (Z)-alkenols and alkenyl acetates with the double bond in any position desired. Bifunctional synthones are used in stereoselective Wittig reactions for the preparation of diunsaturated sex attractants.     

Synthesis of the sulfur amino acids: cysteine and methionine

This review will assess new features reported for the molecular and biochemical aspects of cysteine and methionine biosynthesis in Arabidopsis thaliana with regards to early published data from other taxa including crop plants and bacteria (Escherichia coli as a model). By contrast to bacteria and fungi, plant cells present a complex organization, in which the sulfur network takes place in multiple sites. Particularly, the impact of sulfur amino-acid biosynthesis compartmentalization will be addressed in respect to localization of sulfur reduction. To this end, the review will focus on regulation of sulfate reduction by synthesis of cysteine through the cysteine synthase complex and the synthesis of methionine and its derivatives. Finally, regulatory aspects of sulfur amino-acid biosynthesis will be explored with regards to interlacing processes such as photosynthesis, carbon and nitrogen assimilation.     

Spin-state-dependent oxygen sensitivity of iron dithiolates: sulfur oxygenation or disulfide formation

The oxygen sensitivity of two related iron(III) dithiolate complexes of the ligand [4,7-bis-(2′-methyl-2′-mercatopropyl)-1-thia-4,7-diazacyclononane], (bmmp-TASN)FeCN (1) and (bmmp-TASN)FeCl (2), has been examined. Oxygen exposure of the low-spin complex 1 yields the disulfonate complex (bmmp-O₆-TASN)FeCN (3) as an olive-green solid with characteristic peaks in the IR spectrum at 1262, 1221, 1111, 1021, 947, 800, and 477 cm⁻¹. The corresponding nickel dithiolate, (bmmp-TASN)Ni (4), yields the related disulfonato derivative, (bmmp-O₆-TASN)Ni (5) upon addition of H₂O₂ (IR bands at 1258, 1143, 1106, 1012, 800, and 694 cm⁻¹. Oxygen exposure of the high-spin complex 2 results in disulfide formation and decomplexation of the metal with subsequent iron-oxo cluster formation. Complexes 1 and 2 were examined using density functional theory calculations. A natural bond order/natural localized molecular orbital covalency analysis reveals that the low-spin complex 1 contains Fe–S_thiolate bonds with calculated covalencies of 75 and 86%, while the high-spin complex 2 contains Fe–S_thiolate bonds with calculated covalencies of 11 and 40%. The results indicate the degree of covalency of the Fe–S bonds plays a major role in determining the reaction pathway associated with oxygen exposure of iron thiolates. The X-ray structures of 1, 4, and 5 are reported. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Dynamics of ciguatoxins from Gambierdiscus polynesiensis in the benthic herbivore Mugil cephalus: Trophic transfer implications

This study investigates ciguatoxin dynamics in mullet after controlled feeding of Gambierdiscus polynesiensis cells as a model to characterize the absorption, distribution, retention and accumulation of ciguatoxins into the second trophic level of southwestern Pacific coral reef ecosystems. Mullet (Mugil cephalus) were fed once every other day over a period of 16 days for nine toxic feedings, and ciguatoxin activity was assessed over time in blood and seven tissues using the Neuro2a assay. Within 3 h of feeding on G. polynesiensis cells, ciguatoxins attained maximal blood concentrations, indicating rapid absorption of toxins into the systemic circulation. The time course for distribution of the estimated total tissue burden of ciguatoxin closely followed the time course for blood toxin levels, indicating a rapid distribution of the ciguatoxins throughout the fish body. The large majority (95%) of the ciguatoxin ingested dose was eliminated from the examined fish tissues 24 h after a single toxic meal, indicating little retention potential for ciguatoxin. We found no evidence for ciguatoxin accumulation after nine repeated feedings spaced two days apart, indicating that mullet did not accumulate ciguatoxin. These results provide the first experimental evidence supporting the central tenet of Randall's food chain hypothesis that ciguatoxins enter the food chain by transfer from unicellular algae to herbivorous and detritus-feeding fish. We propose that a time-dependent transformation of oxopene ciguatoxins may be necessary for the concentration of ciguatoxin through higher trophic levels.     

Synthesis of desthio prenylcysteine analogs: sulfur is important for biological activity

N-Acetyl-S-farnesyl cysteine (AFC) is the minimal synthetic substrate for the enzyme Icmt, which methylates prenylated proteins. The desthio-AFC isostere 2 has been synthesized in racemic form. This analog was not an Icmt substrate, but instead a weak inhibitor with an IC50 of approximately 325 microM.     

Synthesis of 5'-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl or halovinyl unit

Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5' were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5'-deoxy-5'-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5'-C6' double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5'-deoxy-5'-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5'-(bromofluoromethylene)-5'-deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-l-homocysteine hydrolases.     

New insights into the stability of alkenes and alkynes, fluoro-substituted or not: a DFT, G4, QTAIM and GVB study

Many undergraduate organic chemistry books do not agree with the order of relative stability of alkenes towards hydrogenation reactions. Although they ascribe the stability of alkenes to the number and spatial position of the alkyl groups attached to the vinyl carbon atoms, results from the quantum theory of atoms in molecules indicate that the influence of an alkyl substituent on the stability of unsaturated hydrocarbons arises from the slight removal of electron density of the π bond, not from donation of their charge density to unsaturated carbon atoms as stated in many text books. There is an inverse relation between delocalization index—the number of shared electrons between two atoms, or Wiberg bond index of C=C bond—and the number of methyl groups attached to the vinyl carbon atoms. Electron withdrawing groups (EWGs) attached to unsaturated carbon atoms of alkenes and alkynes have two different behaviors: slight EWGs (alkyl groups) stabilize unsaturated carbon atoms while the strong EWG destabilizes the unsaturated carbon atoms. Generalized valence bond theory was also used to study the ambiguous behavior of fluorine substituents bonded to vinyl carbon atoms.

Synthesis of fluorous sulfur/carbon/sulfur pincer ligands and palladium complexes: New catalyst precursors for the Heck reaction

Reactions of 1,3-C₆H₄(CH₂Br)₂ and the thiols HSCH₂CH₂R_fn (R_fn = (CF₂)_n−1CF₃; n = 8, 10), or the dithiol 1,3-C₆H₄(CH₂SH)₂ and ICH₂CH₂R_fn, in the presence of carbonate or NaOEt (70-78 °C) give the title ligands 1,3-C₆H₄(CH₂SCH₂CH₂R_fn)₂ (4-R_f8, 58-61%; 4-R_f10, 49-50%). Reactions of 4-R_fn and Pd(OC(O)CF₃)₂ or (PhCN)₂Pd(Cl)₂ (80 °C) afford the title complexes (n/X = 8/OC(O)CF₃ (5-R_f8), 44%; 10/OC(O)CF₃, 58%; 8/Cl (6-R_f8), 45%; 10/Cl, 79%). Both 5-R_f8 and 6-R_f8 are effective catalyst precursors for the Heck reaction of iodobenzene and methyl acrylate (0.21-0.23 mol%, DMF, i-Pr₂NEt, 100-125 °C). However, no active catalyst can be recycled by a subsequent extraction with fluorous solvents. Rather, activity remains in the reddish DMF phase, and is quenched by the addition of mercury. Palladium nanoparticles are visible by transmission electron microscopy. These, or low valent species derived therefrom, are believed to be the active catalysts, in accord with other recent studies involving related non-fluorous and fluorous palladacycles. The CF₃C₆F₁₁/toluene partition coefficients of representative compounds are determined.     

Reaction of 4-hydroxynonenal with some thiol-containing radioprotective agents or their active metabolites

The rate of reaction of several radioprotective agents or their active metabolites with 4-hydroxynonenal (4HNE) was studied and compared to the rate of reaction with cysteine (Cys) and glutathione (GSH). The agents studied were: mercapto ethylamine (MEA); 2(3-aminopropyl) aminoethanethiol (WR1065); S-2-aminoethylisothiouronium bromide-hydrobromide (AET); 1,4-dithiothreitol (DTT); 1,4-dithioerythritol (DTE); N-2(2-mercaptopropionyl)-glycine (MPG); penicillamine hydrochloride (PA); N-acetylcysteine (NAC); 2–3 dimercapto-1 propane sulfonic acid (DMPS); 2,3-dimercaptopropanol (BAL), and meso 2,3 dimercapto succinic acid (DMS). All of them reacted with 4HNE. MEA and WR1065 were the most reactive thiols, and PA and DMS were the least reactive thiols. All the others reacted at rates comparable to or higher than that of cysteine or GSH. The potential role of this type of interactions in the protective action of these drugs against deleterious effects of radiation or carbon tetrachloride is analyzed.     

Titanocene complexes with nonlinear pseudohalide ligands: Synthesis, spectroscopic characterization and crystal structure

Binuclear titanocene complexes [Cp₂Ti(tcm)]₂O (4), [Cp₂Ti(dca)]₂O (5) and [Cp₂Ti(dcnm)]₂O (6) (tcm⁻ = tricyanomethanide, dca⁻ = dicyanamide and dcnm⁻ = dicyanonitrosomethanide) were synthesized in moderate yields by the reaction of Cp₂TiCl₂ (1) with respective alkali metal pseudohalide salts in the aqueous solution. When the reaction was carried out in dry organic solvents, mononuclear compounds Cp₂Ti(tcm)₂ (2) and Cp₂Ti(dca)₂ (3) were isolated. Preparation of dipseudohalide complex Cp₂Ti(dcnm)₂ by this manner was unsuccessful due to decomposition of dcnm ligand resulting in formation of oxygen-bridged compound 6. All prepared compounds were characterized by elemental analysis, NMR, Raman, infrared and UV-Vis spectroscopy. Molecular structures of 2, 4 and 6 (two polymorphs) have been determined by single-crystal X-ray diffraction analysis.     

Synthesis, Solution and Solid State Structure of Titanium-Maltol Complex

The reaction of Cp₂TiCl₂ with two equivalents of maltol (3-hydroxy-2-methyl-4-pyrone) in water, at room temperature and pH of 5.4, leads to a complete replacement of Cp and chloride ligands affording, Ti(maltolato)₂(OH)₂. The complex has been characterized by IR, NMR and ESI-MS spectroscopic and cyclic voltammetry methods. In DMSO-d₆ solution, the complex shows two isomers in a ratio of 4:1, in which one OH signal can be identified per isomer. This suggests that in solution the complex is monomeric, most likely a chiral cis-Ti(maltolato)₂(OH)₂ and trans-Ti(maltolato)₂(OH)₂. The monomeric nature of the complex (in water/methanol 1:1) was verified by ESI-MS spectroscopy, showing a parent peak at 329 m/z. Electrochemical behavior of Ti(maltolato)₂(OH)₂using cyclic voltammetry experiments showed the complex undergoes irreversible reduction in aprotic solvents. In D₂O solution, at pH of 8.4, the ¹H NMR spectrum of the complex shows a mixture of monomer and tetramer Ti(IV)-maltol complexes in a ratio of 1:1. The crystallization of Ti(maltolato)₂(OH)₂ at pH of 8.4 leads to the formation of [Ti₄(maltolato)₈(μ-O₄)] · 18H₂O. A single crystal of [Ti₄(maltolato)₈(μ-O₄)] · 18H₂O was analyzed by X-ray diffraction methods. Solid state structure determination of the Ti-maltol complex showed to be tetrameric, containing two bridging oxides (in cis position) and two bidentate maltol ligands per titanium in a pseudo-octahedral coordination geometry.     

Synthesis of branched-chain sugars: a stereoselective route to sibirosamine, kansosamine, and vinelose from a common precursor

Methyl 4,6-dideoxy-3-C-methyl-4-(N-methyl-N-phenylsulfonylamino)-alpha-L- mannopyranoside and methyl 4-amino-4,6-dideoxy-3-C-methyl-alpha-L-mannopyranoside, derivatives of the branched-chain amino sugars sibirosamine and kansosamine, respectively, were synthesized by nucleophilic ring-opening of methyl 3,4-anhydro-6-deoxy-3-C-methyl-alpha-L-talopyranoside. Catalytic reduction of methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-alpha-L-lyxo-hexopyrano sid-4-ulose gave the axial alcohol methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-alpha-L-talopyranoside, a known precursor to vinelose.     

Inhibition of sulfur mustard-increased protease activity by niacinamide,N-acetyl-L-cysteine or dexamethasone

The pathologic mechanisms underlying sulfur mustard-induced skin vesication remain undefined. Papirmeister et al. (1985) have postulated a biochemical mechanism for sulfur mustard-induced cutaneous injury involving DNA alkylation, metabolic disruption, and enhanced proteolysic activity. We have previously utilized a chromogenic peptide substrate assay to establish that human peripheral blood lymphocytes exposed to sulfur mustard exhibited enhanced proteolytic activity. In this study, compounds known to alter the biochemical events associated with sulfur mustard exposure or to reduce protease activity were tested for their ability to block the sulfur mustard-increased proteolysis. Treatment of cells with niacinamide, N-acetyl-L-cysteine, or dexamethasone resulted in a decrease of sulfur mustard-increased protease activity. Complete inhibition of sulfur mustard-increased proteolysis was achieved by using protease inhibitors (antipain, leupeptin, and 4-(2-aminoethyl)-benzenesulfonylfluoride). These data suggest that therapeutic intervention in the biochemical pathways that culminate in protease activation or direct inhibition of proteolysis might serve as an approach to the treatment of sulfur mustard-induced pathology.Abbreviations APMSF 4-(2-aminoethyl)-benzenesulfonylfluoride, HCI - CPSPA Chromogenic Peptide Substrate Protease Assay - EDTA ethylenediaminetetraacetic acid - HD sulfur mustard - PBL human peripheral blood lymphocytes - pNA p-nitroaniline     

Synthesis of new 2-phosphono-alpha-D-glycoside derivatives by stereoselective oxa-Michael addition to a D-galacto derived enone

The synthesis of new 2-phosphono-alpha-D-glycoside derivatives by stereoselective oxa-Michael addition to an enone derived from D-galactal and containing a phosphonate group is described. Retro-Michael reactions were prevented by tandem acetylation to trap the unstable enolic intermediates. The stereochemistry of the addition products was established by NOESY experiments and explained with molecular mechanics (MM) and density functional theory (DFT) calculations.     

Synthesis, characterization and ethylene polymerization activity of titanium aminopyridinato complexes

Three titanium complexes derived from 2-(2,6-difluoroanilino)pyridine and 2-(2-chloroanilino)pyridine were synthesized and characterized by X-ray diffraction or spectroscopic methods. All titanium complexes have been used to catalyze the polymerization of ethylene in the presence of MAO as cocatalyst. The mono(2,6-difluorophenylaminopyridinato) titanium catalyst was found to be more active in ethylene polymerization than the bis(2,6-difluorophenylaminopyridinato) and bis(2-chlorophenylaminopyridinato) titanium catalysts. ortho-Halogens disturbed the β-elimination transition state of ethylene polymerization and formed higher molar mass polyethylene than their unhalogenated congener. Due to fluxionality, the bis(2-chlorophenylaminopyridinato) titanium catalyst formed broader molar mass distribution than the bis(2,6-difluorophenylaminopyridinato) titanium catalysts.     

Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d]pyrimidines: the development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor

A series of fluoro-substituted 4-(dialkylamino)pyrrolo[2,3-d]pyrimidines was synthesized and their binding affinity for corticotropin-releasing hormone type 1 receptor (CRHR1) was investigated. Compounds 11a and 11b possessed very high CRHR1 affinity (Ki=3.5, 0.91 nM, respectively). They are promising candidates for the development of 18F-containing nonpeptide PET radioligands for CRHR1.     

Synthesis, structure and polymerization behavior of tri- and dichloroaminopyridinato complexes of titanium

Three 2-phenylaminopyridine (Ap) complexes of types ApTiCl₃ and Ap₂TiCl₂ were characterized with X-ray diffraction. The complexes were studied as polymerization catalysts using MAO as cocatalyst. In ethylene polymerization, the catalysts showed moderate activities between 65 and 285 kg PE mol⁻¹ Ti⁻¹ h⁻¹ and the molecular weight distributions were between 2.5 and 4.2, and the molar masses were between 135 000 and 804 000 kg/mol.