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PubMed2002

Distribution of haloacetic acids in the water columns of the Laurentian Great Lakes and Lake Malawi.

Haloacetic acids (HAAs) are persistent and mildly phytotoxic compounds that have been detected in many aquatic environments, including the waters of the Great Lakes. Sources of HAAs, especially of trifluoroacetic acid (TFA), are not well understood. In this study we assessed the influence of urbanization on the concentrations and profiles of HAAs in the Laurentian Great Lakes and in Lake Malawi, an African Great Lake. Vertical depth profiles for these compounds were taken for each of the Great Lakes with additional profiles taken 2 years later for Lakes Erie and Ontario. The results showed that while TFA was relatively constant throughout the water column, the chloroacetic acids (CAAs) varied with depth. There was a trend of increasing TFA proceeding from Lake Superior to Lake Ontario (18-150 ng/L). Total CAA concentrations were relatively constant throughout the lakes (approximately 500 ng/L) with dichloroacetic acid being the most abundant. No bromoacetic acids were detected. In the Detroit River, a connecting channel between Lakes Huron and Erie, the TFA values were similar to those in Lake Huron, but the CAAs levels were higher than in the upstream lakes and dependent on location, indicating inputs from urban areas along the river. These results were compared to those from Lake Malawi, which has a high population density within the watershed but no heavy industry. CAAs were nondetectable, and TFA concentrations were just at the detection limit (1 ng/L). Total HAA in the water column of Lakes Superior and Huron was compared to annual precipitation inputs at a site situated near both lakes. For Lake Huron, precipitation was a minor contributor to the total HAA inventory of the lake, but for Lake Superior precipitation could be the major contributor to the mass of HAA in this lake. Generally, high HAA levels paralleled the degree of industrial activity in the adjacent waters.

Acetates↗
PubMed2004

Kinetics of haloacetic acid reactions with Fe(0).

Detailed kinetic studies of the reactions of haloacetic acids (HAAs) with Fe(0) were performed in longitudinally mixed batch reactors. The reactions of tribromoacetic acid (TBAA), bromodichloroacetic acid, and chlorodibromoacetic acid were mass transfer limited, with corrected mass transfer coefficients of 3.7-3.9 x 10(-4) m/s. The reactions of trichloroacetic acid (TCAA), dichloroacetic acid (DCAA), chloroacetic acid (CAA), and bromoacetic acid (BAA) were reaction limited. Bromochloroacetic acid (BCAA) and dibromoacetic acid (DBAA) were partially reaction limited. For the reaction limited species and partially reaction limited species, intra- and interspecies competition effects were observed. A Langmuir-Hinshelwood-Hougen-Watson kinetic model incorporating a mass transfer term was adopted to account for these effects. The lumped kinetic parameters for the HAAs ranged from 0.04 to 248 microM min(-1) for an iron loading of 0.3 g of Fe/125 mL and followed the trend DBAA > BCAA > TCAA > BAA > DCAA. The adsorption parameters ranged from 0.0007 to 0.0065 microM(-1). The effect of dissolved oxygen (DO) on the reaction of TBAA or BAA with Fe(0) was also investigated. No significant effect of DO on the reaction rate of TBAA, which is a mass transfer limited species, was observed. A lag phase, however, was observed for the reaction of BAA, which is a reaction limited species, until the DO was depleted. Simulations were performed to investigate the potential significance of the reactions of HAAs with Fe(0) in water distribution systems.

Acetates↗
PubMed2004

Chemical and biological characterization of newly discovered iodoacid drinking water disinfection byproducts.

Iodoacid drinking water disinfection byproducts (DBPs) were recently uncovered in drinking water samples from source water with a high bromide/iodide concentration that was disinfected with chloramines. The purpose of this paper is to report the analytical chemical identification of iodoacetic acid (IA) and other iodoacids in drinking water samples, to address the cytotoxicity and genotoxicity of IA in Salmonella typhimurium and mammalian cells, and to report a structure-function analysis of IA with its chlorinated and brominated monohalogenated analogues. The iodoacid DBPs were identified as iodoacetic acid, bromoiodoacetic acid, (Z)- and (E)-3-bromo-3-iodopropenoic acid, and (E)-2-iodo-3-methylbutenedioic acid. IA represents a new class (iodoacid DBPs) of highly toxic drinking water contaminants. The cytotoxicity of IA in S. typhimurium was 2.9x and 53.5x higher than bromoacetic acid (BA) and chloroacetic acid (CA), respectively. A similar trend was found with cytotoxicity in Chinese hamster ovary (CHO) cells; IA was 3.2x and 287.5x more potent than BA and CA, respectively. This rank order was also expressed in its genotoxicity with IA being 2.6x and 523.3x more mutagenic in S. typhimurium strain TA100 than BA and CA, respectively. IA was 2.0x more genotoxic than BA and 47.2x more genotoxic than CA in CHO cells. The rank order of the toxicity of these monohalogenated acetic acids is correlated with the electrophilic reactivity of the DBPs. IA is the most toxic and genotoxic DBP in mammalian cells reported in the literature. These data suggest that chloraminated drinking waters that have high bromide and iodide source waters may contain these iodoacids and most likely other iodo-DBPs. Ultimately, it will be important to know the levels at which these iodoacids occur in drinking water in order to assess the potential for adverse environmental and human health risks.

Acetates↗
PubMed2005

Comparison of haloacetic acids in the environment of the Northern and Southern Hemispheres.

Haloacetic acids (HAAs) are a family of compounds whose environmental concentrations have been extensively studied, primarily in Europe. Depending on the compound, their sources are believed to be both natural and anthropogenic. To better understand possible sources and contribute to the knowledge of the global distribution of these compounds, especially between the Northern and Southern Hemispheres, samples of precipitation, soils, and conifer needles were collected from Canada, Malawi, Chile, and the U.K. Precipitation samples exhibited highest HAA concentrations in collections from Canada, and lowest in those from Malawi. Malawi samples contained measurable levels of monobromoacetic acid (MBA) (56 ng/ L) unlike those from most other locations (< 9 ng/L). Soil HAA concentration levels were highest in the U.K. (e.g., 7.3 ng/g average TCA) and lowest in Malawi (0.8 ng/g average TCA), with Chile having higher levels (4.8 ng/g average TCA) than Canada (3 ng/g average TCA). Malawi soils contained small amounts of MBA (2 ng/g), in common with the two most southern of the 11 Chilean sites. Analysis of soil cores (10-cm depth sliced at 1 cm) from sites in Malawi and Chile showed that trichloroacetic acid (TCA) generally declined with depth while mono- and dichloroacetic acid (MCA and DCA) showed no trend. MCA, DCA, and TCA concentrations in archived U.K. soil samples increased by factors of 2, 4, and 5-fold over 75 years while TFA showed no consistent trend. Monochloroacetic acid (MCA) was detected in pine needles collected from Malawi. U.K. needle samples had the highest concentrations of all chloroacetic acids (CAAs): MCA, 2-18 ng/g; dichloroacetic acid (DCA), 2-38 ng/g; and trichloroacetic acid (TCA), 28-190 ng/g. Conifer needles from Canada and Chile contained CAAs at levels ranging from < 2 to 16 ng/g wet wt. Trifluoroacetic acid concentrations generally declined with increasing elevation in the samples from the Rocky Mountains in western Canada. The results indicate that concentrations of HAAs are greatest in the industrialized Northern Hemisphere but there are significant amounts of these compounds in the less industrialized Southern Hemisphere.

Acetates↗
PubMed2000

Carboxymethylation of cage amines: control of alkylation by metal ion coordination.

Reactions between chloroacetate and both "free" and coordinated forms of the cage amine diaminosarcophagine (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) result in the introduction of between one and four pendent carboxymethyl substituents on the nitrogen atoms of the cage. While at least the first two steps in the reaction of the free ligand have been found to involve only the secondary nitrogen centers, in both the Cu(II) and Co(III) complexes alkylation occurs only at the primary (1,8) centers, the greater ease of achieving a higher degree of alkylation of the Cu(II) complex being attributed to the lower charge of this species causing a lesser reduction of the nucleophilicity of the uncoordinated primary nitrogen atoms. All the new ligands have been characterized by X-ray structure determinations of their Cu(II) or Co(III) complexes. In some cases, this has shown that the methods used to isolate the crystalline complexes result in lactamization of the ligand.

Journal Article↗
PubMed2004

A family of Mn16 single-molecule magnets from a reductive aggregation route.

The synthesis and magnetic properties of three isostructural hexadecametallic manganese clusters [Mn(16)O(16)(OMe)(6)(O(2)CCH(2)Ph)(16)(MeOH)(6)] (1), [Mn(16)O(16)(OMe)(6)(O(2)CCH(2)Cl)(16)(MeOH)(6)] (2), and [Mn(16)O(16)(OMe)(6)(O(2)CCH(2)Br)(16)(MeOH)(6)] (3) are reported. The complexes were prepared by a reductive aggregation reaction involving phenylacetic acid, chloroacetic acid or bromoacetic acid, and NBu(n)()(4)MnO(4) in MeOH. Complex 1 crystallizes in the monoclinic space group C2/c and consists of 6 Mn(IV) and 10 Mn(III) ions held together by 14 mu(3)-O(2)(-), 2 mu-O(2)(-), 4 mu-MeO(-), and 2 mu-O(2)CCH(2)Ph(-) groups. The remaining 14 mu-O(2)CCH(2)Ph(-) ligands, 2 mu-MeO(-) groups, and 6 terminal MeOH molecules constitute the peripheral ligation in the complex. Variable-temperature, solid-state dc magnetic susceptibility measurements on 1-3 in the temperature range 5.0-300 K reveal that all three complexes are dominated by intramolecular antiferromagnetic exchange interactions. Low-lying excited states preclude an exact determination of the spin ground state for 1-3 by magnetization measurements. Alternating current susceptibility measurements at zero dc field in the temperature range 1.8-10 K and a 3.5 G ac field oscillating at frequencies in the 5-1488 Hz range display, at temperatures below 3 K, a nonzero, frequency-dependent chi(M)"signal for complexes 1-3, with the peak maxima lying at temperatures less than 1.8 K. Single-crystal magnetization versus dc field scans down to 0.04 K for complex 1 show hysteresis behavior at <1 K, establishing 1 as a new member of the SMM family. No clear steps characteristic of quantum tunneling of magnetization (QTM) were observed in the hysteresis loops.

Journal Article↗
PubMed2002

Development of an enantioselective synthetic route to neocarzinostatin chromophore and its use for multiple radioisotopic incorporation.

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistry previously developed for the synthesis of a neocarzinostatin core model (4) failed in the requisite 1,3-transposition of an allylic silyl ether when applied toward the preparation of 2 with use of the more highly oxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon a proposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved in a novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. The successful route to 1 and 2 began with the convergent coupling of the epoxydiyne 15, obtained in 9 steps (43% overall yield) from D-glyceraldehyde acetonide, and the cyclopentenone (+)-14, prepared in one step (75-85% yield) from the prostaglandin intermediate (+)-16, affording the alcohol 22 in 80% yield and with > or =20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps with an average yield of 92% and an overall yield of 22%. Key features of this sequence include the diastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylide addition within the epoxy aldehyde 82, using Masamune's lithium diphenyltetramethyldisilazide base (85% yield); selective esterification of the diol 84 with the naphthoic acid 13 followed by selective cleavage of the chloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and elimination of the tertiary hydroxyl group within intermediate 88 using the Martin sulfurane reagent (79% yield). Reductive transposition of the product epoxy alcohol (58) then formed neocarzinostatin chromophore aglycon (2, 71% yield). Studies directed toward the glycosylation of 2 focused initially on the preparation of the N-methylamino --> hydroxyl replacement analogue 3, an alpha-D-fucose derivative of neocarzinostatin chromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For the synthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discovery that the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed the alpha-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotection of 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route was readily modified for the preparation of singly and doubly (3)H- and (14)C-labeled 1, compounds unavailable by other means, for studies of the mechanism of action of neocarzinostatin in vivo.

Antibiotics, Antineoplastic↗
PubMed2003

Incorporation of unprotected heterocyclic side chains into peptoid oligomers via solid-phase submonomer synthesis.

Peptoids (N-substituted glycines) are an important class of biomimetic oligomers that have made a significant impact in the areas of combinatorial drug discovery, gene therapy, drug delivery, and biopolymer folding in recent years. Sequence-specific peptoid oligomers are easily assembled from primary amines by the solid-phase submonomer method. However, most amines that contain heterocyclic nitrogens in the side chain do not incorporate efficiently. We present here a straightforward revision of the submonomer method that allows efficient incorporation of unprotected imidazoles, pyridines, pyrazines, indoles, and quinolines into oligomers as long as 15 monomers in length. This improved method uses chloroacetic acid instead of bromoacetic acid in the acylation step of the monomer addition cycle, and allows for the incorporation of new side chains that should enable the synthesis of peptoids with entirely new properties.

Acylation↗
PubMed2005

Geometry and cooperativity effects in adenosine-carboxylic acid complexes.

NMR experiments and theoretical investigations were performed on hydrogen bonded complexes of specifically 1- and 7-15N-labeled adenine nucleosides with carboxylic acids. By employing a freonic solvent of CDClF2 and CDF3, NMR spectra were acquired at temperatures as low as 123 K, where the regime of slow hydrogen bond exchange is reached and several higher-order complexes were found to coexist in solution. Unlike acetic acid, chloroacetic acid forms Watson-Crick complexes with the proton largely displaced from oxygen to the nitrogen acceptor in an ion pairing structure. Calculated geometries and chemical shifts of the proton in the hydrogen bridge favorably agree with experimentally determined values if vibrational averaging and solvent effects are taken into account. The results indicate that binding a second acidic ligand at the adenine Hoogsteen site in a ternary complex weakens the hydrogen bond to the Watson-Crick bound carboxylic acid. However, substituting a second adenine nucleobase for a carboxylic acid in the trimolecular complex leads to cooperative binding at Watson-Crick and Hoogsteen faces of adenosine.

Adenosine↗
PubMed2005

Parallel synthesis: a new approach for developing analytical internal standards. Application to the analysis of patulin by gas chromatography-mass spectrometry.

The polymer-assisted reaction of 4-(hydroxymethyl)furan-2(5H)-one (4HM2F) with 21 carboxylic acids using polystyrene-carbodiimide (PS-carbodiimide) yielded an ester library. Four of the esters, (5-oxo-2,5-dihydrofuran-3-yl)methyl acetate (IS-1), (5-oxo-2,5-dihydrofuran-3-yl)methyl butyrate (IS-2), (5-oxo-2,5-dihydrofuran-3-yl)methyl 2-methylpropanoate (IS-3), and (5-oxo-2,5-dihydrofuran-3-yl)methyl chloroacetate (IS-4), were tested as internal standards for the quantification of patulin in apple juice by gas chromatography-mass spectrometry in the selected ion monitoring mode (GC-MS-SIM). The developed method combines an AOAC official extractive step and a GC-MS-SIM analysis. Using a chromatographic column containing trifluoropropylmethylpolysiloxane as the stationary phase and IS-1 as the internal standard, it was possible to perform an accurate and precise quantification of underivatizated patulin in apple juice at concentrations down to 6 microg/L. A detection limit of 1 microg/L was established.

Beverages↗
PubMed1991

Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection.

The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl]propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of [3H]AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid [( 3H]KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity [3H]KAIN binding (IC50 = 40 microM) as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation. Both antagonists showed very weak effects on the excitatory effects of NMDA. Compound 7 was a poor antagonist of excitation by quisqualic acid (2), whereas 14 did not affect excitation by this nonselective AMPA receptor agonist. On cat spinal neurones, both 7 and 14 reduced excitations by 1 and KAIN, but, again, the excitatory effects of 2 were much less sensitive. Compound 14 and, in particular, 7 effectively protected rat striatal neurones against the neurotoxic effects of KAIN, whereas the toxic effects of 1 were reduced only by 7. Neither antagonist showed protection against the cell damage caused by intrastriatal injection of the NMDA agonist quinolinic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1981

Haloacetamido analogues of 2-amino-2-deoxy-D-mannose. Syntheses and effects on tumor-bearing mice.

Haloacetamido analogues (fluoro, chloro, and bromo) of 2-deoxy-2acetamido-D-mannose and their tetra-O-acetates were prepared from D-mannosamine hydrochloride, with either chloroacetic or bromoacetic anhydride or by dicyclohexylcarbodiimide-activated condensation with fluoroacetate followed by acetylation. Comparative specific rotations and 13C and 1H NMR spectra were consistent with a beta configuration for the tetra-O-acetylated derivatives, 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(bromoacetamido)-beta-D-mannose and the corresponding analogue of glucose inhibited [3H]thymidine incorporation into mouse L1210 leukemia cells by 50% (IC50) at concentrations between 6 and 9 microM. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(chloroacetamido)-beta-D-mannose was 3-fold more active in the thymidine-incorporation assay (143 +/- 24 microM, IC50) than was the corresponding analogue in the glucose series (425 +/- 62 microM; p = 0.05). All of the haloacetamido free sugars, as well as the tetra-O-acetates of the fluoroacetamido analogues in the glucose, galactose, and mannose series, were inactive in the thymidine incorporation assay at 1mM. In the mannose series the tetra-O-acetylated chloroacetamido and bromoacetamido analogues, as well as the bromoacetamido free sugar, could be administered at relatively high in vivo tolerated doses compared to the corresponding analogues in the galactose and glucose series. These three mannose analogues produced high proportions of cures of Ehrlich tumor-bearing B6D2F1 mice, whereas in the galactose and glucose series only the tetra-O-acetylated bromoacetamido analogues had previously produced in vivo chemotherapeutic activity.

Acetamides↗
PubMed1985

Potential radiosensitizing agents. 7. 4(5)-Iodo-5(4)-nitroimidazole derivatives.

A series of 4(5)-iodo-5(4)-nitro-1-substituted-imidazoles has been synthesized and tested for their ability to selectively radiosensitize hypoxic Chinese hamster cells (V-79) to the lethal effect of radiation. The reaction of 4(5)-iodo-5-(4)-nitroimidazole with 1,2-epoxy-3-methoxypropane and ethyl alpha-chloroacetate produced two isomeric products in each case, which were identified by their NMR spectra. The ethyl esters were further reacted with 3-picolylamine to produce corresponding amides. The 5-iodo-4-nitroimidazole-1-N-(3-picolyl)acetamide on further reaction with m-chloroperbenzoic acid produced the corresponding N-oxide. These compounds were generally more toxic to V-79 cells than the 2-nitroimidazole derivatives and were found to be more effective radiosensitizers in vitro. The 5-iodo-4-nitroimidazole derivatives were more efficient as sensitizers than the 4-iodo-5-nitroimidazole derivatives, and the sensitizing efficiency of this class of agents was found to have significant correlation with their partition coefficients.

Animals↗
PubMed1987

Methotrexate analogues. 30. Dihydrofolate reductase inhibition and in vitro tumor cell growth inhibition by N epsilon-(haloacetyl)-L-lysine and N delta-(haloacetyl)-L-ornithine analogues and an acivicin analogue of methotrexate.

Analogues of methotrexate (MTX) with strong alkylating activity were prepared by replacing the L-glutamate side chain with N omega-haloacetyl derivatives of L-lysine and L-ornithine. Haloacetylation was accomplished in 30-40% yield by reaction of the preformed L-lysine and L-ornithine analogues of MTX with p-nitrophenyl bromoacetate or chloroacetate in aqueous sodium bicarbonate at room temperature. All four haloacetamides were potent inhibitors in spectrophotometric assays measuring noncovalent binding to purified dihydrofolate reductase (DHFR) from L1210 cells. In experiments designed to measure time-dependent inactivation of DHFR from L1210 cells and Candida albicans, the N epsilon-(bromoacetyl)-L-lysine and N delta-(bromoacetyl)-L-ornithine analogues gave results consistent with covalent binding, whereas N epsilon- and N delta-chloroacetyl analogues did not. The N delta-(bromoacetyl)-L-ornithine analogue appeared to be the more reactive one toward both enzymes. Amino acid analysis of acid hydrolysates of the L1210 enzyme following incubation with the bromoacetamides failed to demonstrate the presence of a carboxymethylated residue, suggesting that alkylation had perhaps formed an acid-labile bond. In growth inhibition assays with L1210 cultured murine leukemia cells, the four haloacetamides were all more potent than their nonacylated precursors but less potent than MTX. The greater than 40,000-fold MTX-resistant mutant cell line L1210/R81 was only partly cross-resistant to the haloacetamides. An analogue of MTX with acivicin replacing glutamate was a potent inhibitor of DHFR from chicken liver and L1210 cells but was 200 times less potent than MTX against L1210 cells in culture.

Acetates↗
PubMed1996

Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine.

Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl+ ++)-alpha,beta-D-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2',3'-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N1-substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.

Alkylation↗
PubMed2000

Oxazolium-derived azomethine ylides. External oxazole activation and internal dipole trapping in the synthesis of an aziridinomitosene.

Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO(2)CH(2)CH(2)OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe(3)(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.

Aziridines↗
PubMed2002

Synthesis of monoacyl A-ring precursors of 1alpha,25-dihydroxyvitamin D3 through selective enzymatic hydrolysis.

An efficient synthesis of monoacylated 1alpha,25-dihydroxyvitamin D3 A-ring precursors 15, 16, 18, and 19 has been described through an enzymatic hydrolysis process. Candida antarctica A lipase (CAL-A) hydrolyzes the C-5 acetate ester in trans stereoisomers 9 and 13, with complete and high selectivity, respectively. In the case of cis isomers 11 and 14, Chromobacterium viscosum lipase (CVL) is the enzyme of choice, exhibiting opposite selectivity for these two enantiomers. This lipase selectively catalyzes the hydrolysis at the C-3 acetate in diester 11 and at C-5 position in diester 14. It is noteworthy that through a hydrolysis reaction CAL-A and CVL allow the synthesis of the four A-ring monoacetylated precursors of 1alpha,25-dihydroxyvitamin D3, precursors which are complementary to those obtained by the enzymatic acylation process. In addition, with excellent yield CVL selectively hydrolyzes the C-3 chloroacetate ester instead of the C-5 acetate in diester 22, a key intermediate in the synthesis of new A-ring modified 1alpha,25-dihydroxyvitamin D3 analogues.

Burkholderia cepacia↗
PubMed2004

Diastereoselective synthesis of cularine alkaloids via enium ions and an easy entry to isoquinolines by aza-Wittig electrocyclic ring closure.

In preliminary communications, we reported the diastereoselective synthesis of cularine and sarcocapnine via the intramolecular ring closure of nitrenium and oxenium ions, a new highly diastereoselective reductive methylation with (+)-8-phenylmenthyl chloroacetate followed by reduction with sodium borohydride, and a facile entry to the isoquinoline precursors by aza-Wittig electrocyclic ring closure. We now report the full details of the syntheses of (+)-O-demethylcularine, (+)-cularine, (+)-sarcocapnidine, (+)-sarcocapnine, and (+)-crassifoline and describe different methods of synthesis of their precursors.

Acetates↗