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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.

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.

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-...

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.

Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S5-S4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of0.1 mg/mL and Ki values ofor = 10 nM.

Enantioselective and diastereoselective syntheses of the title antifun- gal natural products and some of their diastereoisomers are described. Key steps include the diastereoselective 1,6-addition of bislactim et- her (14) and a stereoselective deprotonation of ketone (17) using lit- hium (S,S)-bis(1-phenylethyl)amide as a chiral base. All natural produ- cts possess the (S)-configuration at C-1 of the substituted cyclohex- (en)yl residues of the C-terminal amino acids, which contradicts the assignments in the literature. At physiological pH most of the dipepti- des are instable and react by an intramolecular 1,4-addition with the formation of 6-oxoperhydroindoles

A combination of diastereoselective borohydride reduction of the subs- tituted α-bromo-propiophenone [(±)-2] and microbial-assisted hydrolysis of its corresponding bromohydrin acetate using Rhizopus nigricans, led to the chiral epoxide, (-)-6. The regiospecific opening of this epoxide, produced pure (-)-virolin [1], whose absolute configuration could be assigned through this sequence as 7S,8S. It is possible, by selecting the appropriate starting materials, to obtain different chiral threo neolignans of the 8.0,4'-type and to predict their configuration

A series of β-alkyl-α,β-unsaturated trifluoromethyl ketones have been prepared from the corresponding α-acetylenic trifluoromethyl ketones. The addition of sulfur nucleophiles was shown by chemical and 19 F NMR studies to proceed exclusively by 1,4-addition with no indication of any 1,2-addition products. The unsaturated trifluoromethyl ketones have been shown to be effective inhibitors of rat cytosolic glutathione-S-transferase

4,4'-Bi(cyclobutene-1,2-diones), novel compounds derived from squaric acid, here named bisquaryls, were prepared for the first time either by the palladium-catalyzed oxidative dimerization of (tri-n-butylstannyl)cyclobutene-1,2-diones (providing symmetrically substituted bisquaryls) or by a palladium-copper cocatalyzed cross-coupling of 3-substituted-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-diones with 3-halo-4-substituted-3-cyclobutene-1,2-diones (providing a route to unsymmetrically substituted bisquaryls). The novel parent bisquaric acid is a very strong BrOnsted acid that apparently fully ionizes on dissolution; only one pK a value (pK a = -4.49) was observed

A novel tetracyclic pyridone carboxylic acid with a thiazolidine ring, 1,2-dihydro-9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo -5H- thiazolo[3,2-a]quinoline-4-carboxylic acid (4a), and variants with a nitrogen atom (4b) or carbonyl group (4c) in the place of the 10-position oxygen atom of 4a were prepared and tested for antibacterial activity and inhibitory activity on DNA gyrase from Escherichia coli KL-16. The in vitro antibacterial potency with regard to the 10-position atom was found to be of the following order; O > NCH3 = C = O. The IC50 values for DNA gyrase inhibition activity for the 4a, 4b, and 4c compounds were 0.33, 0.53, and 0.67 g/mL, respectively. The activity of 4a, in which the C-3 methyl group and C-5 of ofloxacin (2a) were connected with a sulfur atom to restrict the conformation of 2a, was more potent than that of 2a against both Gram-positive and -negative bacteria, except for Pseudomonas aeruginosa. Compared to the tetracyclic pyridone carboxylic acid 1a, which has a flat thiazole ring, compound 4a showed comparable or slightly more potent activity against both Gram-positive and -negative bacteria, except for P. aeruginosa.

Ru(II)- or Cu(I)-induced radical reaction of CF 2 ClCCl 2 . radical (2), regioselectively derived from CF 2 ClCCl 3 , to trimethylsilyl enol ethers and a ketene silyl acetal yields (β,β,γ-trichloro-γ,γ-difluoropropyl)carbonyl compounds 5 as the intermediates. Spontaneous dehydrochlorination affords [β-chloro-β-(chlorodifluoromethyl)vinyl]carbonyl compounds 4. Reductive dechlorination of 4 with zinc gave γ,γ-difluoroallyl ketones 7a-e and an ester 7f. In some cases, Ni(O)-catalyzed reduction with zinc is superior than the simple hydrodechlorination

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

A general, regioselective synthesis of substituted benzocyclobutenedione monoacetals is reported. Palladium-catalyzed coupling of a variety of 4-chlorocyclobutenones with 3-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione 2-(ethylene acetal) and heating up to 70-100 o C produces substituted benzocyclobutenedione monoacetals in good to excellent yields. This chemistry is presumed to proceed through palladium-catalyzed formation of a 3-(1-oxo-2-cyclobuten-4-yl)-3-cyclobutene-1,2-dione-2-(ethylene acetal) followed by a thermally induced ring opening to a dienyl ketene and subsequent six-electron electrocyclic ring closure and tautomerization. 2,3-Disubstitued 4-chlorocyclobutenones afford palladium intermediates which couple exclusively at the least-substituted allylic terminus. 2,3,4-Trisubstituted 4-chlorocyclobutenones have not been studied in detail; however, preliminary results suggest that regioselective allylic cross-coupling can be achieved. The methodology described provides an expedient and efficient route to previously difficult-to-prepare benzocyclobutenedione derivatives. These function as important synthetic intermediates in a variety of reactions developed in these and other laboratories

The synthesis of the peptidyl difluoro ketone 1, an inhibitor of interleukin-1β converting enzyme (ICE), was accomplished by a route beginning with the reaction of BrZnCF 2 CO 2 Et (2) with (2S)-1-(tert-butyldimethylsilyl)-4-oxo-2-azetidinecarboxaldehyde (3) to give a mixture of epimeric alcohols 4 and 5. Conversion of alcohol 5 to 1 was carried out by a sequence including the novel coupling of β-lactam 17 and BOC-Ala-O(succinimide) to form lactone 18. The difluoro ketone was found to exist as a mixture of diastereomeric γ-hydroxy lactone tautomers in chloroform solution

A new method of appending seven- and eight-membered rings to cycloakenes is described. Treatment of selected alkene precursors with an ω-bromoalkyl ketene or a keteniminium salt leads to haloalkyl cyclobutanone formation. Tri-n-butylin hydride promoted ring expansion then yiels the annulated product. Since the initial cyclobutanone is cis fused, the final product is alao produced stereospecifically with a cis ring fusion

Stannylcarbamate 1 proved to be a selective agent for generating organotin(IV) enolates from α-halo ketones. Thus, a Darzens reaction was achieved under mild and neutral conditions. The reaction took place without any side reactions and even with aliphatic α-halo ketones bearing enolizable α'-hydrogens. Various types of α,β-epoxyketones and esters were obtained in the one-pot reaction. The stereoselectivity of the reaction was influenced by changing the halogen substituent of the α-halo ketones and by additives

A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3- carboxylic acids has been prepared. These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position. In this paper we report the full details of the asymmetric synthesis of this series of compounds. Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity. Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.

The furan-fused chlorocyclobutanone 6 undergoes reaction with O, N, S, C nucleophiles at a much slower rate than its pyran homolog, which is attributed to a reluctance to enolization. Instead of subsititution products, rearranged products were formed.Enolization of 6 (6=chlorooxabicyclo[3.2.0]heptanone)toward the ring jonction in the oxabicycloheptanone is greatly retarded compared to the oxabicyclooctanone and proceeds only with strong nucleophiles(MeO - , - CH(COOEt) 2 at 20°C or with N 3 - on heating).The cine substitution products were not isolated but underwent further transformations;with oxygen nucleophiles such as AcO - or HO - ,when heating was required, the products were seven- or five- membered-ring lactones.These were formed either via vinylketenes or by opening of the cyclobutanone and/or the tetrahydrofuran ring.PhS - gave an ipso substitution product (presumably via electron transfer) that underwent acid-catalysed rearrangement to a naphtofuran

Several new fluorone derivatives including 2,4,5,1-tetraiodo-6-hydroxy-3-fluorone, 2,4,5,1-tetrabromo-6-hydroxy-3-fluorone, and 2,4-diiodo-6-methoxy-3-fluorone were synthesized and their spectral and photophysical properties investigated

Chlorine substituents on the alkene control the regioselectivity of the cyclization of 5-hexenyl or 6-heptenyl radicals generated by oxidation of an acetoacetate ester or 1,3-diketone with Mn(OAc) 3 -2H 2 O. 6-Exo-cyclization of the radicals obtained by oxidation of benzoylacetone derivatives 10 and 13, containing a chlorine on the terminal double bond carbon, gives α-chloroalkyl radicals that add to the aromatic ring to give 11 and 16, respectively. Loss of HCl leads to naphthols 8 and 17 indicating that this reaction may be useful for aureolic acid synthesis

The alkaline hydrolysis of 2,2,2-trichloro-1-phenylethanone (TCA) in the presence of cationic (CTABr and CTACl), anionic (SDS), and nonionic (Tween-80) surfactants was studied. The PPIE model was shown to apply sucessfully to this multistep reaction

The syntheses of (-)-cannabidiol and (-)-cannabidiol dimethyl ether were accomplished via fragmentation of an appropriately substituted 9-bromocamphor derivative. A new method of α-arylation of 3,9-dibromocamphor was shown to provide a variety of α-arylated camphor derivatives in good yields

Chlorobycyclooctanone 3 on reactin with H 2 O-Et 3 N in acethonitrile at 20 o C produced in high yield four complex dimeric compounds 4-7. The novel structures produced by C-C bond formation between tertiary centers were revealed by NMR and X-ray diffraction. Pathways leading from 4 or its diastereomer 14 to cage compounds 5-7 indicate the importance of proximity effects in these transformations

Hypervalent iodine oxidation of O-silylated phenols bearing various types of aminoquinones at the para position in 2,2,2-trifluoroethanol gave azacarbocyclic spiro dienones in good yields. Using this method, the first total synthesis of discorhabdin C, which was isolated from the sponge of Latrunculia du Bocagein New Zealand, was achieved

(CH 3 ) 3 SiCF 3 reacts with fluoro ketones in the presence of excess KF in CH 3 CN to produce alkoxides derive from formal addition of CF 3 - to the carbonyl carbon. These alkoxides may be isolated as such or acidified to the corresponding alcohols

When 1,3,5(10)-estratrien-3-ols are treated with N-fluorobis[(trifluoromethyl)sulfonyl]imide in chloroform solution the ortho and para fluorination products are formed. In contrast, when acetic acid is used as a solvent, fluorination in the para position occurs selectively and 10β-fluoro-3-oxo-1,4-estradiene derivatives are formed in high yields

A series of (benzoylphenyl)piperidines has been synthesized and evaluated for activity as immunomodulators. Several of these compounds show good activity in primary screening on the basis of the lymphocytes mitogenic response to Con A, PHA, and PWM. A chloro group in position 4 of the benzoyl moiety as well as an amino group (or a carbamate derivative) para to the piperidine nucleus seems to be essential for activity. The depicted compounds may be considered as the first examples of a new series of immunomodulators.

The reaction of equimolar amounts of ketones or ketone trimethylsilylenol ethers with organyltellurium trichlorides in boiling benzene produces α-(dichloroorganyltelluro) ketones. The yields are good in the reaction of ketones and ketone silylenol ethers with (p-methoxyphenyl)tellurium trichloride; however, the reaction with aliphatic tellurium trichlorides gives good results only with ketone silyl enol ethers; reaction with ketones gives low yields of the α-(dichloroorganyltelluro) ketones. α-[Dichloro(p-methoxyphenyl)-telluro]acetophenone and α-[dichloro(p-methoxyphenyl)telluro]pinacolone afford the corresponding α-chloroketone in good yield on pyrolysis. Under similar conditions, the α-[dichloro(p-methoxyphenyl)telluro]-cycloalkanones give low yields of the α-chloro ketones. Reaction of the α-(dichloroorganyltelluro) ketones with halogens (Cl 2 , Br 2 ) gives the corresponding α-halo ketone even in the case of the cycloalkanones

By judicial choice of reaction pathway and conditions, such that the base-catalyzed displacement of chloro ketone was carried out on the less acidic free amine, (R)-(−) SK&F 93505 was produced in seven synthetic steps from (R)(+)-2-chloropropionic acid

The synthesis of a number of substituted 2-tert-butyladamantan-2-ols from the corresponding ketones is described. In addition to these addition reactions, some unexpected rearrangements were observed. Reaction mechanisms are proposed to rationalize the experimental results. 13 C NMR spectra of some adamantanes are discussed in terms of substituent interaction effects

1-Chloro-3,3-dimethylbicyclo [2.2.2] octan-2-one (5) does not react with diphenyl phosphide ions (4) in liquid ammonia in the dark in 240 min, but under irradiation (30 min). We suggest that the bridgehead chloride 5 reacts by the S RN 1 mechanism of nucleophilic substitution and that the 2-oxo substituent increases the reactivity of the chloride due to the LUMO of the carbonyl group

In order to control the Diels-Alder reactivity of the very labile title compound 1, experiments designed to modify the carbonyl group have been carried out. Diazomethane reacts with 1 in cold methanol to give a spirooxirane which undergoes Diels-Alder dimerization orders of magnitude slower than dienone 1 at room temperature. Trimethylsilyl cyanide yields a trimethylsilyl cyanohydrin, a stable derivative of 1 that dimerizes only at elevated temperatures, yet retains reactivity as a Diels-Alder diene

The polar extract of an undescribed Verongid sponge from the island of Molokai yielded three new bromotyramines. Two compounds terminate in a chlorocyclopentanedione enamine moiety. Their structures were elucidated by NMR spectra measured at -30 degrees C. The third compound is the N-methyl derivative of a known compound. This structure was determined by NMR spectra measured at room temperature.