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2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity.

Substrate inhibition of enzymes is one of the main obstacles encountered frequently in industrial biocatalysis. Haloketone reductase SsCR was seriously inhibited by substrate 2,2′,4′-trichloroacetophenone. In this study, two essential loops were found that have a relationship with substrate binding by conducting X-ray crystal structure analysis. Three key residues were selected from the tips of the loops and substituted with amino acids with lower hydrophobicity to weaken the hydrophobic interactions that bridge the two loops, resulting in a remarkable reduction of substrate inhibition. Among these variants, L211H showed a significant attenuation of substrate inhibition, with a Ki of 16 mM, which was 16 times that of the native enzyme. The kinetic parameter kcat/Km of L211H was 3.1 × 103 s−1 mM−1, showing the comparable catalytic efficiency to that of the wild-type enzyme (WT). At the substrate loading of 100 mM, the space time yield of variant L211H in asymmetric reduction of the haloketone was 3-fold higher than that of the WT.

A new access to the 6a-hydroxypterocarpan variabilin was established. Key step of this concise total synthesis is a challenging cyclization of a haloketone via halogen–metal exchange and subsequent intramolecular addition to the carbonyl function.

Ripostatins are polyene macrolactones isolated from the myxobacterium Sorangium cellulosum. They exhibit antibiotic activity by inhibiting bacterial RNA polymerase (RNAP) through a binding site and mechanism that are different from those of current antibacterial drugs. Thus, the ripostatins serve as starting points for the development of new anti-infective agents with a novel mode of action. In this work, several derivatives of ripostatins were produced. 15-Desoxyripostatin A was synthesized by using a one-pot carboalumination/cross-coupling. 5,6-Dihydroripostatin A was constructed by utilizing an intramolecular Suzuki cross-coupling macrolactonization approach. 14,14'-Difluororipostatin A and both epimeric 14,14'-difluororipostatins B were synthesized by using a Reformatsky type aldol addition of a haloketone, Stille cross-coupling, and ring-closing metathesis. The RNAP-inhibitory and antibacterial activities are presented. Structure-activity relationships indicate that the monocyclic keto-ol form of ripostatin A is the active form of ripostatin A, that the ripostatin C5-C6 unsaturation is important for activity, and that C14 geminal difluorination of ripostatin B results in no loss of activity.

The palladium-catalysed α-chloro ketone methoxycarbonylation and allylic alkylation reactions can be efficiently combined to provide a new catalytic domino reaction. The first, carbonylative, step generates the β-keto ester, which acts as the nucleophile in a subsequent allylation step. The use of allyl phenates in combination with Xantphos ligand are the key features allowing one to obtain the allylated β-keto esters in good yields.

Chlorinated derivatives of aliphatic ketones are a class of organic compounds poorly characterized by both mass spectra and chromatographic retention indices up to present. It is caused by objective difficulties of isolation of individual products from reaction mixtures formed in the result of non-selective chlorination of parent carbonyl compounds. Nevertheless the differences of GC retention indices for structurally analogous chlorination products of different ketones and initial substrates indicate the constancy depending on the number and position of chlorine atoms in the molecules. This feature permits us to use the simplest kind of additive schemes in identification of such chlorinated derivatives, including diastereomeric α,α'-dichloro-k-alkanones (k>2). Hence, the identification of chlorination products of aliphatic ketones becomes possible for any compounds of this class without using mass spectrometric data only in the result of accurate measurement of their GC retention indices.

Reactions of electron-poor α-haloketones with (N-isocyanimino) triphenylphosphorane in the presence of aromatic carboxylic acids proceed smoothly at room temperature and in neutral conditions to afford disubstituted 1,3,4-oxadiazole derivatives in high yields. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:368–372, 2010; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20626

We previously reported on the design and synthesis of 1-[((hetero)aryl- or piperidinylmethyl)amino]-2-phenyl-3-(1 H -1,2,4-triazol-1-yl)propan-2-ols showing various degrees of antifungal activity against Candida albicans and Aspergillus fumigatus strains. Now we have identified a series of 1-[(1 H -indol-5-ylmethyl)amino] derivatives which exhibited potent MICs ( −1 ) against C. albicans strain. The synthesis and SAR behind the indole scaffold will be discussed.

While natural organic matter (NOM) surrogates are established in disinfection byproduct (DBP) research, their use in fractionation studies is rare. To understand how surrogates relate to drinking waters, a range of NOM surrogates were fractionated with XAD resins. Their trihalomethane (THM), haloacetic acid (HAA), haloacetaldehyde, haloacetonitrile, and haloketone formations after chlorination were recorded. While compounds with higher log K(ow) values behaved as hydrophobic acids, fractionation of the more hydrophilic compounds did not clearly correlate to the log K(ow). High HAA formation from ferulic and aspartic acids and 1,1,1-trichloropropanone (1,1,1-TCP) formation from 3-oxopropanoic acid were notable. Three amino acids, asparagine, aspartic acid, and tryptophan, formed significant levels of dichloroacetonitrile (DCAN) and trichloroacetaldehyde (TCA). Formation of DBPs did not correlate to any compound physical property; however, there were several correlations between DBP groups. The most significant were between dichloroacetic acid (DCAA) and dichloroacetonitrile (DCAN), DCAN and TCA, and dichloroacetaldehyde (DCA) and trichloroacetaldehyde, indicating the possibility of similar relationships in natural waters.

Nitropolychlorobutadienes are valuable precursors for highly functionalized acyclic or (hetero)cyclic compounds. In this 8th part of our synthetically oriented series we focus on the application of these versatile starting materials in the synthesis of analogs of the heterocyclic insecticides imidacloprid™ and thiacloprid™, and the acyclic counterpart clothianidin™. In addition to the main synthetic part, leading to imidazolidines or oxazolidines, further promising types of compounds derived by subsequent chemical modifications, are introduced. Most of the new compounds show high insecticidal activity.

Dentre os compostos orgânicos halogenados que podem ser encontrados na água distribuída à população, destacam-se: trialometanos, ácidos haloacéticos, haloaldeídos, halocetonas, halofenóis e halopicrinas. O presente trabalho teve como objetivo avaliar o efeito da formação de 22 subprodutos com a utilização dos pré-oxidantes: cloro, ozônio e peroxônio. A formação de subprodutos foi observada em água preparada com adição de substâncias húmicas extraídas de solo turfoso, por meio do uso da pré-oxidação, presença e ausência de coagulação, filtração e pós-cloração. Os subprodutos foram quantificados por cromatografia gasosa com detetor de captura de elétrons. Os resultados obtidos mostraram que o uso de pré-oxidantes alternativos, ozônio e peroxônio, associados à coagulação, filtração e pós-cloração, formam quantidades pequenas de subprodutos. When chlorine is used as preoxidant, the formation of halogenated organic byproducts found in water treated and distriduted to the population, are: trihalometane, haloacetic acids, haloaldehyde, haloketone, halophenol and halopicrin. This research was performed to evaluate the formation potential of 22 byproducts using the following preoxidants: chlorine, ozone and peroxone. The formation of byproducts was simulated in water prepared with the addition of humic substances extracted from peat soil by the use of preoxidants, coagulation, filtration, and post-chlorination. Byproducts have quantified by gas chromatography with electron capture detector. The results obtained showed that the use of alternative preoxidants, such as ozone and peroxone, associated with coagulation, filtration, and post-chlorination form a low concentration of byproducts.

Three types of 5alpha-androstane and ergostane analogues of brassinolide, containing a fluorine atom in either the 3alpha or the 5alpha positions or in 3alpha and 5alpha positions, were prepared using standard operations (reaction of 3beta-alcohols with (diethylamino)sulfur trifluoride, cleavage of epoxide with HF in py or BF 3.Et 2O). The 5alpha-fluorine was found to affect chemical reactivity (e.g., electrophilic addition to the Delta (2)-double bond) as well as physical properties (e.g., NMR, chromatographic behavior) of the products. Cytotoxicity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control and their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. The equivalence of F and OH groups was observed in some of the active compounds. The anticancer and the brassinolide-type activity do not correlate with each other: ergostane derivatives were most active in the former test while androstane derivatives were best in the latter.

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.

Carboxylesterases metabolize numerous exogenous and endogenous ester-containing compounds including the chemotherapeutic agent CPT-11, anti-influenza viral agent oseltamivir, and many agrochemicals. Trifluoromethyl ketone (TFK)-containing compounds with a sulfur atom beta to the ketone moiety are some of the most potent carboxylesterase and amidase inhibitors identified to date. This study examined the effects of alkyl chain length (i.e., steric effects) and sulfur oxidation state upon TFK inhibitor potency (IC50) and binding kinetics (k(i)). The selective carboxylesterase inhibitor benzil was used as a non-TFK containing control. These effects were examined using two commercial esterases (porcine and rabbit liver esterase) and two human recombinant esterases (hCE-1 and hCE-2) as well as human recombinant fatty acid amide hydrolase (FAAH). In addition, the inhibition mechanism was examined using a combination of 1H NMR, X-ray crystallography, and ab initio calculations. Overall, the data show that while sulfur oxidation state profoundly affects both inhibitor potency and binding kinetics, the steric effects dominate and override the contributions of sulfur oxidation. In addition, the data suggest that inclusion of a sulfur atom beta to the ketone contributes an increase (approximately 5-fold) in inhibitor potency due to effects upon ketone hydration and/or intramolecular hydrogen bond formation. These results provide further information on the nature of the TFK binding interaction and will be useful in increasing our understanding of this basic biochemical process.

Reaction of selenazadienes with α-haloketones gave 5-acyl-2-amino-1,3-selenazoles in high yields.

The synthesis and evaluation of N -{4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}- l -glutamic acid ( 2 ) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase ( K i = 0.50 μM), whereas it was inactive ( K i > 100 μM) against E . coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC 50 = 6.0 μM).

Cyclic tetrapeptides containing trifluoromethyl and pentafluoroethyl ketone as zinc binding functional group were synthesized as potent HDAC inhibitors. Evaluation by human HDAC inhibition assay and p21 promoter assay showed that these inhibitors are promising anticancer agents.

Successive alkylation of 5-(3-phenylthioureido)-3H-imidazole-4-carboxamides with alkyl halides and chloroacetone gave (N-oxopropylimidazolyl)isothioureas, which were easily converted into derivatives of purine and imidazopyrazinone. In the case of ethyl 5-(3-phenylthioureido)-3H-imidazole-4-carboxylate, primary alkylation occurs at the N atom of the imidazole ring. Reactions of 5-(3-phenylthioureido)-3H-imidazole-4-carboxamides with haloketones afforded a number of 4-hydroxy-2-imidazolyliminothiazolidines and 2-imidazolylimino-Δ4-thiazolines.

Dermal contact with some organic disinfection by-products (DBPs) such as trihalomethanes in chlorinated drinking water has been established to be an important exposure route. We evaluated dermal absorption of two haloketones (1,1-dichloropropanone and 1,1,1-trichloropropanone) and chloroform while bathing, by collecting and analyzing time profiles of expired breath samples of six human subjects during and following a 30-min bath. The DBP concentrations in breath increased towards a maximum concentration during bathing. The maximum haloketone breath concentration during dermal exposure ranged from 0.1 to 0.9 microg / m(3), which was approximately two orders of magnitude lower than the maximum chloroform breath concentration during exposure. Based on a one-compartment model, the in vivo permeability of chloroform, 1,1-dichloropropanone, and 1,1,1-trichloropropanone were approximated to be 0.015, 7.5 x 10(- 4), and 4.5 x 10(- 4) cm / h, respectively. Thus, haloketones are much less permeable across human skin under normal bathing conditions than is chloroform. These findings will be useful for future assessment of total human exposure and consequent health risk of these DBPs.

A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.

A series of simplified alpha-keto heterocycle, trifluoromethyl ketone, and formyl substituted folate analogues lacking the benzoylglutamate subunit were prepared and examined as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase).

Several [18F]-labeled α-trifluoromethyl ketones have been synthesized. Reactions of 2,2-difluoro-1-aryl-1-trimethylsiloxyethenes (1a–d) with [18F]-F2 at low temperature produced [18F]-labeled α-trifluoromethyl ketones (2a–d). Radio-labeled products were isolated by purification with column chromatography in 22–28% yields, decay corrected (d.c.) in three runs per compound. Radiochemical purity was >99% with specific activities 15–20 GBq/mmol at the end of synthesis (EOS). The synthesis time was 35–40 min from the end of bombardment (EOB). This one-step simple method is highly useful for the radiochemical synthesis of potential biologically active [18F]-labeled α-trifluoromethyl ketones for PET imaging. Copyright © 2003 John Wiley & Sons, Ltd.

Carbon-14 labeled 4-[4-[2-[2-[bis(4-chlorophenyl)methoxyethylsulfonyl] [1-14C]ethoxy]phenyl]-1,1,1-trifluoro-2-butanone was prepared in a six step radioactive synthesis from 2-bromo[1-14C]acetic acid. The overall radiochemical yield was 2.2%. The specific activity of the final product was found to be 42μCi/mg with a radiochemical purity of >98%. Copyright © 2002 John Wiley & Sons, Ltd.

Dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, were synthesized and evaluated for their influence on nitric oxide production. Some of them, chalcones 1 , 5 , 7 , 10 , 11 and 17 , inhibited NO production with an IC 50 in the submicromolar range; 17 is especially noteworthy because of its potency (IC 50 30 nM). These effects were not the consequence of a direct inhibitory action on enzyme activity but the inhibition of enzyme expression.

Various 3-cyclopropanecarbonyloxy-2-cyclohexen-1-one 1 derivatives have been synthesized and tested as inhibitors of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) from pig liver. The inhibition results indicated that well-positioned dicarbonyl groups as well as the cyclopropyl group of 1 were essential for potent inhibition. Substitution at the 2-position of the ring system has a significant effect on inhibitor potency, while the 5-position can undergo substantial variations and retain inhibitor potency. In the compounds examined, 2-chloro substituted 12 is the best inhibitor of all with IC 50 of 15 nM, the rest of the synthesized analogues were less potent inhibitors than the parent compound.

Solid-phase peptide synthesis in the N-to-C direction, opposite to the classical C-to-N direction of peptide synthesis, provides the synthetically versatile C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, particularly as protease inhibitors. Elaboration of peptide mimetics on the solid-phase would facilitate synthesis of peptide mimetic combinatorial libraries. This report describes an effective strategy for solid-phase inverse peptide synthesis based on readily available amino acid tert-butyl esters. The potential of this approach for peptide mimetic synthesis is demonstrated by the solid-phase synthesis of two peptide trifluoromethylketones.

To assess the potential of intermolecular hydroacylation reactions as a new fluorine-18 labeling method, model reactions of [18F]fluorobenzaldehyde with three different olefins (1-hexene (2a), allylbenzene (2b), and 3-phenoxypropene (2c)) in the presence of Wilkinson's catalyst were performed. The procedure gave high radiochemical yields (38–62%) of [18F]fluorophenylketones with short reaction times (15 min). The intermolecular hydroacylation reaction provides a new method for the preparation of fluorine-18 labeled compounds. Copyright © 2002 John Wiley & Sons, Ltd.

A new synthesis of N-enoyloxazolidin-2-ones has been performed by electrochemical reduction of α,α′-di- and trichloroketones in aprotic solvent in the presence of Evans’ chiral auxiliaries (oxazolidin-2-ones). The electrochemical reduction of trichloroketones via a chlorocyclopropanone as intermediate allows a Favorskii rearrangement involving trichloroketones and oxazolidin-2-ones. N-Enoyloxazolidin-2-ones have been obtained this way under mild reaction conditions and in good to high yields.

The critical parameters and normal boiling temperatures of five fluorinated ethers (1,1,1,2,4,4,4-heptafluoroisobutyl trifluoromethyl ether, tert-perfluorobutyl methyl ether, 1,1,1,2-tetrafluoro-2-...

4-(2-Pyridinylamino)-1,1,1-trifluoro-3-penten-2-ones 3, obtained from the reaction of commercially available 2-aminopyridine derivatives and 4-methoxy-1,1,1-trifluoro-3-penten-2-one 2, were converted to 6-(dimethylamino)-4-(2-pyridinylamino)-3,5-hexadien-2-ones 4 by treatment with dimethylformamide dimethyl acetal. Azannulation of hexadienones 4 afforded 4-(2-pyridinylamino)-2-trifluoromethylpyridines 5 and 2-(trifluoroacetylmethylene)pyrido[1,2-a]pyrimidines 6, classes of compounds particularly interesting from a chemical and biological point of view.

Substrate-like difluoroketones have been prepared as potential inhibitors of MMP-13. Weak inhibition was seen with the key target 2. This and the more potent activity of intermediate 7b illustrates that hydrated ketones can be used to inhibit MMP-13 and perhaps other members of this class of enzymes.

An efficient synthesis of [4-14C]-5α-Androstan-16α-bromo-3β-ol-17-one (1) via the intermediate [4-14C] testosterone (8) is described. This compound targets cellular metabolic pathways and clinical trials to HIV-viral pathogenicity are promising. Copyright © 2000 John Wiley & Sons, Ltd.

Using a combination of solid phase synthesis for the preparation of N-substituted-N-acylglycines 7 followed by solution-phase ring transformation of trifluoromethylacyl munchnone intermediate 8, a library of 200 trisubstituted-5-trifluoromethylketo (TFMK) imidazoles 9 was prepared. In a sublibrary, bromoacetate resin 4 was treated with 5 amines in parallel to give N-substituted glycines 5 followed by acylation with 12 acid chlorides to provide, upon cleavage from the resin, 60 individual N-substituted-N-acylglycines 7. The glycines 7 were converted to munchnones 8 by treatment with trifluoroacetic anhydride followed by reaction with benzamidine to give trisubstituted-5-TFMK-imidazoles 9. The structural content of the library was analyzed using PlateView of the LCMS results, and individual members were isolated by automated preparative LCMS.

The Dakin-West reaction of N-alkoxycarbonyl-N-alkyl-alpha-amino acids (1a-j) with trifluoroacetic anhydride in the presence of pyridine gave alpha-amido trifluoromethyl ketones (2a-j), in which probable intermediates were mesoionic 1,3-oxazolium-5-olates (munchnones). The diastereoselective reduction of 2a-f with NaBH4 gave the threo-aminoalcohols (5a-f), which may be explained by the Felkin-Anh model. This was confirmed by converting 5a-f into trans-5-trifluoromethyl-2-oxazolidinones (6a-f) in good yields.

A novel pathway for the preparation of 3, 4-dihydro-2H-1λ6-benzo[e][1, 2]thiazine 1, 1-dioxides 3 via an orthomethyl lithiation/cyclization reaction of N-acyl-o-toluenesulfonamides 5 is reported. Readily available N-acyl-o-toluenesulfonamides 5 were treated with 2 eq of n-BuLi at -78°C-0°C to give the corresponding sultams 6 in moderate to good yields. The resulting sultams 6 were converted to saturated sultams 3, which can be considered as one carbon-extended homologues of the Oppolzer sultams 1, in high yields by hydrogenation. Studies on the scope and limitation of this annulation for the preparation of sultams are discussed. Demonstration of the feasibility of using the sultams 3 templates for an electorophilic fluorinating agent is also described.

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

The 1,2-dithiolanes 1 and 2 and the 1,2-dithianes 3–5 were prepared from the dibromoalkanones 14–18 and Li2S2. Whereas the five-membered systems 1 and 2 were readily formed, the six-membered derivatives 3–5 occurred always together with various amounts of the monothiacyclopentanes 11–13. The 1,3-dithia compounds 6–10 were prepared from the dibromoalkanes 19, 20, 14–16 and HSCH2SH in pyridine. The synthesis of the precursors 14–20 is described. Flavour evaluation showed that particularly 2, but also 1 and 3–8 (previously isolated from meat flavour model systems) should contribute with their fatty, spicy, roasty, mushroom and sulphury notes to the total meat flavour complex. © 1998 John Wiley & Sons, Ltd.

The π values of benzalacetones (BZ) and trans-1, 1, 1-trifluoro-4-phenyl-3-buten-2-ones (TF) with a substituent on the benzene ring were analyzed by the directional Hommett-type treatment. The correlation equation showed that πBZ and πTF values are altered from the π value of monosubstituted benzenes, πPhX, mainly by the change in the hydrogen bonding behavior of the variable substituent caused by the electron-withdrawing fixed substituent. The log k' values for BZ and TF derived from reversed-phase liquid chromatography (RPLC) were correlated with log P values determined by using different compositions of methanol-phosphate buffer (pH 7.4) as eluents. A good linear correlation was obtained at 50% methanol concentration.

Side-chain fluorinated 15-ketosterols are potent regulators of sterol synthesis. For investigations of their metabolism, we have prepared 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15-one and its 7α-methyl and 8(14)-saturated derivatives with one deuterium or tritum atom at C-23. The isotopic hydrogen was introduced by reduction of 23-iodo-15-ketosterols with tributyltin deuteride or tritide. Mass spectral analyses of the deuterated sterols showed incorporation of one deuterium in the side chain, and 2H and 13C NMR showed that deuterium was present only at C-23. The tritiated sterols had specific activities of 82-179 mCi/mmol and showed high radiochemical purities. © 1998 John Wiley & Sons, Ltd.

The protease inhibitor (S)-1-chloro-3-[(p-tolylsulfonyl)amino]-7-amino-2-[5,5,6,6-3H]heptanone ([ 3 H]TLCK) was prepared in an overall 41% radiochemical yield with a specific activity of 1.6 Ci/mmol in a'one-pot' 3 step sequence beginning with (S)-6-[[(1,1-dimethylethyl)oxy]carbonyl]-2-(p-tolylsulfonyl)amino[4,4,5,5- 3 H]hexanoic acid. The latter was prepared with a specific activity of 123 Ci/mmol in a 3 step sequence beginning with the stereospecific enzymatic hydrolysis of the commercially available racemic 2-acetylamino-6-[[(1,1-dimethylethyl)-oxy]carbonyl]aminohexan-4-ynoic acid, followed by tosylation and then palladium catalyzed reduction of the triple bond under tritium.

Erythro N-protected α-amino epoxides, derived from α-amino acids bearing functionalized side chains, were synthesized. The key synthetic step is a stereoselective reduction of the corresponding haloketone either to the halohydrin or directly to the epoxide. The side chains include ester, ether and alcohol, nitro guanidine, carbamate and amine functional groups, derived from aspartate and glutamate, serine, arginine, and lysine, respectively. The epoxides derived from lysine and Nϖ-nitro-arginine exhibited selective inactivation of the cysteine proteases papain and cathepsin B, while they failed to inactivate the serine protease trypsin.

Ro41-0960 (3,4-dihydroxy-5-nitro-2′-fluorobenzophenone) is a potent, fluorine containing COMT inhibitor. In order to map catechol-O-methyltransferase (COMT) in vivo with PET, no-carrier-added [18F]Ro41-0960 was synthesized by the nucleophilic aromatic substitution of [18F]fluoride for 2′-nitro on 3,4-dimethoxy-5,2′-dinitrobenzophenone, followed by hydrolysis with HBr. During the course of this study it was found that [18F]fluoromethane ([18F]CH3F) was generated as the side product of nucleophilic aromatic substitution reaction. Various precursors with different hydroxyl protecting groups were then investigated for the effects on this side reaction. © 1997 John Wiley & Sons, Ltd.

Sixteen ketone electrophores were synthesized (4′-pentafluorobenzyloxyacetophenone, 1, and fifteen analogs thereof). As intended, each gave a high response by gas chromatography with electron capture detection (GC-ECD) as well as GC with detection by electron capture mass spectrometry (GC-EC-MS). Each spectrum by the latter technique consisted of a single major ion. As a representative compound, 1 was converted to a corresponding olefin, N-hydroxysuccinimide ester, which, in turn, was attached covalently to a DNA oligomer. Detection of the latter species spotted onto a nylon membrane was achieved by the sequence permanganate oxidation (which reformed and thereby released 1), hexane extraction, silica solid phase extraction and GC-EC-MS (giving a peak for 1). These results demonstrate potential for olefin-release group electrophores to function as multiplicity labels in assays involving DNA probes.

The standard-enthalpies of formation of the following fluorinated β-diketones at T =298.15 K were determined from their enthalpies of combustion measured using rotating bomb calorimetry. Δ f H ° m 1,1,1-Trifluoropentan-2,4-dione(1) −1034.5±2.3 1,1,1-Trifluorohexan-2,4-dione(1) −1049.4±2.4 1,1,1-Trifluoro-5-methyl-hexan-2,4-dione(1) −1095.4±2.4 1,1,1-Trifluoro-5,5-dimethyl-hexan-2,4-dione(1) −1118.0±2.6 1,1,1-Trifluoro-5-methyl-heptan-2,4-dione(1) −1105.6±2.7 1,1,1,5,5,5-Hexafluoropentan-2,4-dione(1) −1623.0±4.3 1,1,1,2,2,3,3-Heptafluoro-7,7-dimethyl-octan-4,4-dione(1) −1988.3±4.9 4,4,4-Trifluoro-1-(2-furanyl)-butan-1,3-dione(cr) −1050.8±2.6 4,4,4-Trifluoro-1-(2-naphthyl)-butan-1,3-dione(cr) −901.0±3.1 With enthalpies of vaporization and sublimation, the enthalpies of formation of these β-diketones were derived for the gaseous state in their enol and keto forms. Where applicable, the enthalpies of formation in the gaseous state correlated satisfactorily with values estimated by group additivity methods.

A simple and efficient synthesis of novel 6-aminomethyl-tetrahydroindol-4-ones, which are butyrophenone analogues of molindone, is described. These compounds exhibit potent affinities for D2 and 5-HT2A receptors in vitro. The most active compounds, 6d (QF 0408B) and 6e (QF 0409B), with pKi (5-HT2A/D2) ratios of 1.32 and 1.17 respectively, show an antipsychotic profile according to Meltzer's classification.