Showing papers on "Bicyclic molecule published in 1998"
TL;DR: In this article, the intramolecular nonbonded 1,5-type S···O interactions are recognized in the crystalline structures of the (acylimino)thiadiazoline derivatives (1−3) as angiotensin II receptor antagonists.
Abstract: The intramolecular nonbonded 1,5-type S···O interactions are recognized in the crystalline structures of the (acylimino)thiadiazoline derivatives (1−3) as angiotensin II receptor antagonists. The relative stability of the nonbonded 1,5-type S···O interaction was investigated using the X-ray crystallographic analyses and the ab initio MO calculations (HF/3-21G*, 6-31G*, and 6-311+G**) of the simplified model compounds (6, 7, and 9). The concept of mimic-fused bicyclic heterocycles consisting of fairly stable nonbonded S···O interaction seems to be an efficient approach toward the design and development of various drugs.
244 citations
Patent•
16 Feb 1998TL;DR: In this paper, a disubstituted bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E, in which A, B, Ar, Het and Ra are defined as in claim 1.
Abstract: The invention relates to new disubstituted bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E, in which A, B, Ar, Het and Ra are defined as in claim 1. The invention also relates to their tautomers, their stereoisomers, their mixtures, and their salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, thus represent valuable intermediate products for the production of the other compounds of the general formula (I). Furthermore, the compounds of the above general formula (I), in which E stands for a RbNH-C(=NH)-group, have valuable pharmacological properties, in particular in inhibiting thrombin and prolonging thrombin time.
150 citations
TL;DR: In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]p iperazine (p-MPPI, 31) (Kd = 0.36 nM), showed high binding affinities
Abstract: In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]p iperazine (p-MPPI, 31) (Kd = 0.36 nM), as potential ligands for 5-HT1A receptors were reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [123I]-31 and rendered this agent obsolete as an in vivo imaging agent in humans. To improve the in vivo stability of 31, a series of cyclized amide analogues were designed and synthesized. In vitro binding, metabolic stability, and in vivo biodistribution of these new derivatives were investigated. Several five-membered-ring isoindol-1-ones displayed very high in vitro binding affinity, especially 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-6-nitro-3-phenyl-2, 3-dihydroisoindol-1-one, 15, 3-hydroxy-6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}- 3- phenyl-2,3-dihydroisoindol-1-one, 18, and 6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-3-phenyl-2, 3-dihydroisoindol-1-one, 21, which showed Ki values of 0.05, 0.65, and 0.07 nM, respectively. The affinities for 5-HT1A receptors of other cyclized amide derivatives, 5-(4-bromophenyl)-1-{2-[4-(2-methoxyphenyl)- piperazin-1-yl]ethyl}pyrrolidin-2-one, 25, 5-(4-iodophenyl)-1-{2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethyl}pyrrolidin-2-one, 27, and 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dihydro- isoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectively. Compared to [125I]-31, iodinated cyclized amide derivatives [125I]-21 and [125I]-27 displayed a slower metabolism in human liver microsomal and cytosolic preparations. Biodistribution of [125I]-21 and [125I]-27 in rats (after an i.v. injection) displayed moderate to low brain uptakes with little or no specific localization in hippocampal region, where 5-HT1A receptors are concentrated. These data indicate that the new iodinated ligands showed high binding affinities and better metabolic stability but displayed unexpectedly low selective binding to 5-HT1A receptors in vivo. Additional structural modifications may be needed to correct the unfavorable properties displayed for these iodinated cyclized amide derivatives for in vivo biodistribution in rats.
148 citations
TL;DR: A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r, and many of these active compounds show improved potency compared to the reference compound FUT-175.
Abstract: A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).
138 citations
TL;DR: Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones 9-12 and 18 were considered as annulated analogues of HEPT (1-[(2-hydroxyethoxyethoxy)methyl]-6-(phenylthio)-thymine), and some of these compounds were also found active against HIV-1.
Abstract: Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones 9−12 and 18 were considered as annulated analogues of HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), and some of these compounds were also found active against HIV-1, the most active one being 2,3-dihydro-5-[(3,5-dimethylphenyl)methyl]-3-ethoxy-6-ethyl-7H-thiazolo[3,2-a]pyrimidin-7-one (10b). S-Alkylation of 5-alkyl-6-(arylmethyl)-2-thiouracils 1−4 was performed with 2-bromoacetaldehyde acetals to furnish the S-[bis(alkoxy)ethyl] derivatives 5−8 and with allyl bromide to furnish S-allyl derivatives 17. The target compounds 9−12 were obtained by an N1 regioselective intramolecular cyclization reaction of silylated 5−8 using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as the catalyst. Treatment of the S-allyl derivatives 17 with bromine in dry methylene chloride afforded the 3-(bromomethyl) derivatives 18.
128 citations
126 citations
122 citations
Patent•
27 Aug 1998TL;DR: In this article, a method for forming a film of ruthenium oxide on the surface of a substrate by employing the techniques of chemical vapor deposition to decompose precursors of rUThenium having the formula: L y RuX z where L is a neutral or monoanionic ligand selected from the group consisting essentially of linear hydrocarbyls.
Abstract: A method is provided for forming a film of ruthenium or ruthenium oxide on the surface of a substrate by employing the techniques of chemical vapor deposition to decompose precursors of ruthenium having the formula: L y RuX z where L is a neutral or monoanionic ligand selected from the group consisting essentially of linear hydrocarbyls, branched hydrocarbyls, cyclic hydrocarbyls, cyclic alkenes, dienes, cyclic dienes, trienes, cyclic trienes, bicyclic alkenes, bicyclic dienes, bicyclic trienes, tricyclic alkenes, tricyclic dienes, tricyclic trienes; fluorinated derivatives thereof; derivatives thereof additionally containing heteroatoms such as a halide, Si, S, Se, P, As, N or O; and combinations thereof; where X is a pi-bonding ligand selected from the group consisting of CO, NO, CN, CS, nitriles, isonitriles, trialkylphosphines, trialkylphosphites, trialkylamines, and isocyanide, and where subscripts y and z have a value of from one (1) to three (3); or L 1 Ru(CO) 4 where L is a neutral or monoanionic ligand selected from the group including linear hydrocarbyls, branched hydrocarbyls, cyclic hydrocarbyls, cyclic alkenes, dienes, cyclic dienes, trienes, cyclic trienes, bicyclic dienes, and bicyclic trienes.
120 citations
TL;DR: In contrast to their hydrocarbon analogues which exhibit only nematic mesophases, poly{5-[[[2,5]-bis[(n-(dimethylsiloxyl)alkoxy)benzoyl)oxy]benzyl]oxy]carbonyl]bicyclo[2.2.1]hept-2-ene}s and their low-molar-mass model compounds exhibit smectic C mesomorphism as mentioned in this paper.
Abstract: In contrast to their hydrocarbon analogues which exhibit only nematic mesophases, poly{5-[[[2‘,5‘-bis[(4‘‘-(n-(dimethylsiloxyl)alkoxy)benzoyl)oxy]benzyl]oxy]carbonyl]bicyclo[2.2.1]hept-2-ene}s and their low-molar-mass model compounds exhibit smectic C mesophases. Since nematic liquid crystals can be forced into layers by terminating their hydrocarbon substituents not only with fluorocarbon segments but also with flexible siloxane segments, this supports the hypothesis that the smectic mesomorphism of amphiphilic molecules containing linear fluorocarbon segments is due primarily to the immiscibility of the hydrocarbon and fluorocarbon segments, rather than to a shape persistence of “mesogenic perfluoroalkyl rods”. The 2,5-bis[(4‘-(n-(oligodimethylsiloxyl)alkoxy)benzoyl)oxy]toluenes mimic both the phases formed by the polymers and the general temperatures of their transitions and are thereforeexcellent models of the polymers. The 5-{[[2‘,5‘-bis[(4‘‘-(n-(oligodimethylsiloxyl)alkoxy)benzoyl)oxy]benzyl]oxy]car...
103 citations
TL;DR: In this paper, the intramolecular hydroamination of hindered alkenes has been developed as a versatile route to heterocyclic systems, which tolerates a wide variety of substitution patterns.
Abstract: The intramolecular hydroamination of hindered alkenes has been developed as a versatile route to heterocyclic systems. The current process utilizes the unhindered catalyst system [CpTMS2LnMe]2 (Ln = Sm, Nd) to effect the cyclization of hindered amino olefins, providing products containing quaternary centers. The process tolerates a wide variety of substitution patterns, allowing the construction of monocyclic as well as fused and bridged bicyclic heterocycles. Two experimental procedures were employed in this study: one without solvent, minimizing waste streams, the other in deuterated solvents, allowing NMR monitoring of the reaction. The yield of each reaction was high, with NMR analysis of the reactions in progress showing clean conversion from starting material to a single product in most cases.
92 citations
TL;DR: Semiempirical calculations indicate that the thermodynamic stabilities of the three alternative isomeric ring systems are similar to that of the classical penam or penem structure, and ab initio methods suggest that the N-fused bicyclic β-lactams are considerably more electrophilic than the corresponding C-fusion compounds.
Abstract: Described in this article are studies of structurally novel [3.2.0]bicyclic β-lactam ring systems that are isomeric to those of the penicillin, penem, and clavulanic acid families of antibiotics, but which have the lactam functionality arranged in alternative orientations within the four-membered ring. Semiempirical calculations indicate that the thermodynamic stabilities of the three alternative isomeric ring systems are similar to that of the classical penam or penem structure, and ab initio methods reveal that the LUMO energies of the two C-fused ring structures 11 and 12 are more than 1 eV lower than that of 2-azetidinone, but 0.22 to 0.73 eV higher than that of the penem ring 13. The LUMO energy of the N−S fused penem structure 14 is about 0.2 eV lower than that of 13. These studies also suggest that the N-fused bicyclic β-lactams are considerably more electrophilic than the corresponding C-fused compounds. Several of the new heterocyclic rings were synthesized using a two-step cyclization strategy t...
TL;DR: The results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the same strand, forming intrastrand cross-linked adducts.
Abstract: The formation and isolation of the antitumor drug cisplatin analogue cis-[PtCl2(Hmtpo-N3)2]·2H2O (1) (where Hmtpo = 4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine) by reaction of Hmtpo with K2[PtCl4] in HCl (0.5 N) is reported. This complex crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 15.215(2) A, b = 9.629(1) A, c = 13.115(3) A, β = 97.40(2)°, and Z = 4. The molecular structure shows that Pt is in an almost square planar environment, PtN2Cl2, which has a cis configuration. The Hmtpo ligands show a head to head orientation in the solid state and nonrestricted rotation about the Pt−N bonds in solution. The reactivity of the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methylcytosine (1-MeC) has been investigated by 1H NMR spectroscopy at 45 °C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t1/2 ≈ 5 days) by displacement of Cl-, producing cis-[Pt(mtpo-N3)2(9-EtGH-N7)2], which is similar to the major cross-link adduct of cisplatin wi...
TL;DR: The antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.
Abstract: A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 μg/mL. The structure−activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]-3-methyl-2-pyridyl)methyl]thio]-1H-benzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felis model (125 μmol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to ...
TL;DR: A series of bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl] alkanes have been synthesized and were converted into bis-[1,0,3-b]-1,3,4 -thiadiazol-4-yl alkanes which exhibited activity with MIC in the range 3-12.5 micrograms/ml.
Abstract: A series of bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl] alkanes have been synthesized and were converted into bis-[1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-4-yl] alkanes. The newly synthesized compounds were characterized by analytical IR, NMR and mass spectral studies. Some of the newly synthesized compounds were screened for their antibacterial properties and exhibited activity with MIC in the range 3–12.5 μg/ml.
TL;DR: It was found that those which possess a homoveratrylamino moiety exhibited superior potency and the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1.
Abstract: Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed. The 4-benzyl-3,4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1,4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.
TL;DR: Modified dipeptides have been used successfully for the generation of a variety of small organic and heterocyclic combinatorial libraries, including linear urea, polyamine, hydantoin, thiohydantoin and cyclic urea; cyclic thiourea and bicyclic guanidine.
TL;DR: Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma.
Abstract: The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[520]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist It contains the α-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57% Structure−activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl
TL;DR: A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands, leading to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin.
Patent•
26 Jun 1998TL;DR: In this article, a 2-substituted 4,5-diaryl imidazoles with p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity are presented.
Abstract: Novel 2-substituted 4,5-diaryl imidazoles in which: i) the nitrogen atom at the 1 position is substituted by a trialkylsilyl-containing substituent, or ii) the substituent at the 2 position is arylalkyl, arylsulfonyl, arylthio arylseleno, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, amino or hydrazino, or mono- or bicyclic N-heterocyclyl in which the N containing ring has six ring members, are provided, in particular compounds of Formula (I) wherein R1, R2, R3 and R4 are as defined, in free or pharmaceutically-acceptable acid additon salt or physiologically-cleavable ester form, which have p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity. The compounds are used as pharmaceuticals for treating TNFα and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
TL;DR: In this article, the authors compared 11C-methyl triflate with [11C]methyl iodide as a labelled precursor in the synthesis of PET radioligands through 11Cmethylation of amide and thiol functions.
Abstract: [11C]Methyl triflate was compared with [11C]methyl iodide as a labelled precursor in the synthesis of PET radioligands through 11C-methylation of amide and thiol functions. [11C]NMSP, [11C]flumazenil and [11C]methionine were prepared in 50–75% radiochemical yields using smaller amounts of precursors, shorter reaction times and lower reaction temperatures than previously used when these compounds were prepared from [11C]methyl iodide. By minimizing the amount of base used in the synthesis of [11C]methionine from [11C]methyl triflate and L-homocysteine thiolactone in water a lower amount (1–2%) of D-[11C]methionine was obtained. The results demonstrate that [11C]methyl triflate is compatible with low concentrations of aqueous sodium hydroxide, which enable its use in the preparation of PET radioligands through 11C-methylation of amide and thiol functions. © 1998 John Wiley & Sons, Ltd.
TL;DR: In this article, the diastereoselectivity of the photocycloaddition of benzaldehyde to furan was determined (exo/endo = 212:1) and compared with the reaction of other carbonyls compounds and carbonyl analogues.
Abstract: The diastereoselectivity of the photocycloaddition of benzaldehyde to furan was determined (exo/endo = 212:1) and compared with the reaction of other carbonyl compounds and carbonyl analogues. These results were compared with Paterno−Buchi reactions of cycloalkenes and cyclic enol ethers. An increase in steric demand of the α-substituent in benzoyl compounds led to a change in exo/endo-selectivity for furan cycloadditions that was not observed for cycloalkenes or cyclic enol ethers. Different ISC-reactive conformers with enhanced spin−orbit coupling are postulated as a reasonable explanation for the stereoselectivities observed. Additionally, solvent effects were studied, demonstrating the influence of photoinduced electron-transfer steps on the regio- and diastereoselectivity of Paterno−Buchi reactions with 2,3-dihydrofuran in polar solvents. Two bicyclic oxetanes (8 and 10) were characterized by X-ray structure analysis.
TL;DR: In this article, the Schrock and Grubbs Cl2(Cy3P)2RuCHPh (2) carbenes gave diverse monocyclic and bicyclic β-lactam dienes including derivatives of 1-azabicyclo[4.2.0]octan-8-one, 1-aza-1-cyclo[5.2]nonan-9-one and its 6-thia, 6-aza, and 6-oxa analogues.
Abstract: 4-Acetoxy-2-azetidinone and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyl)-oxyethyl]-2-azetidinone were converted into 4-alkenyloxy-, 4-(N-allyltoluene-4-sulfonamido)-, 4-(allylthio)-, and 4-alkenyl-2-azetidinone systems. In addition, 4-acetoxy-2-azetidinone and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyl)-oxyethyl]-2-azetidinone were converted into β-lactam dienes via sequential C-4 substitution using unsaturated alcohols, allyl mercaptan, N-allyltoluene-4-sulfonamide, and allyl(chloro)dimethylsilane followed by N-allylation. Crossed metathesis of β-lactam alkenes with styrene partners and ring closing metathesis of β-lactam dienes using the Schrock [(CF3)2MeCO]2Mo(CHCMe2Ph)(NC6H3-2,6-iso-Pr2) (1) or Grubbs Cl2(Cy3P)2RuCHPh (2) carbenes gave diverse monocyclic and bicyclic β-lactam systems including derivatives of 1-azabicyclo[4.2.0]octan-8-one, 1-azabicyclo[5.2.0]nonan-9-one and its 6-thia, 6-aza, and 6-oxa analogues, 7-oxa-1-azabicyclo[6.2.0]octan-10-one, 8-oxa-1-azabicyclo[7.2.0]octan-...
TL;DR: In this article, several anthelmintic coumarins based on the β-hydroxyketoamide (BKA) template have been prepared and shown that this template remains valid over a wide range of changes to the coumarin moiety allowing for the inclusion of carbocyclic, bicyclic, and heter-cyclic rings.
TL;DR: As the conformational flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also increased, and those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5- HT4 receptor antagonist activity.
Abstract: A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus. The endo-3-tropanamine derivatives in the indazole and benzimidazolone series possessed greater 5-HT4 receptor affinity than the corresponding indole analogues. 5-HT4 receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic heterocycle. In a series of 1-isopropylindazole-3-carboxamides, replacement of the bicyclic tropane ring system with the monocyclic piperidine ring system or an acyclic aminoalkylene chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4 receptor antagonist activity. While some of these compounds displayed high affinity for other neurotransmitter receptors (in particular, 5-HT3, alpha1, and 5-HT2A receptors), as the conformational flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also increased. From this series of compounds, we identified LY353433 (1-(1-methylethyl)-N-[2-[4-[(tricyclo[3.3.1.1(3, 7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl]-1H-indazole-3- carboxamide) as a potent and selective 5-HT4 receptor antagonist with clinically suitable pharmacodynamics.
TL;DR: Because of the selective building of a quarternary carbon center and good yields in the formation of bicyclic structures 34c-h, the reaction was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of the Aspidosperma family.
Abstract: A set of cyclic enol ethers derived from 2,3-dihydrofuran 35 and 3,4-dihydropyran 8 with a varying substitution pattern at the olefinic system were synthesized. Evans's ligand 5 with Cu(I)OTf was found to be an effective catalyst in the cyclopropanation reaction between cyclic enol ethers 14, 19, 28-31, and 33 and ethyl diazoacetate 6 to give diastereoselectivities up to exo/endo = 95:5 and enantioselectivities higher than 95% in nearly all cases. Because of the selective building of a quarternary carbon center and good yields in the formation of bicyclic structures 34c-h, the reaction was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of the Aspidosperma family. After acid-induced ring opening of bicyclic compound 34f to lactone 40 followed by LiAlH(4) reduction to the masked aldehyde 41, a reaction with tryptamine gave intermediate 42. This alcohol was efficiently converted into the indole alkaloid (+)-quebrachamine 7 in an overall yield of 37% starting from the chiral synthon 34f. Moreover it revealed the absolute configuration of the quarternary center of the cyclopropanation product 34f to be S.
TL;DR: In this article, a method for the construction of a fused cyclohexadiene ring on C60 based on a nickel-promoted cycloaddition of 1,6-diynes is described.
Abstract: A novel method for the construction of a fused cyclohexadiene ring on C60 based on a nickel-promoted [2+2+2] cycloaddition of 1,6-diynes is described. Treatment of C60 with terminal 1,6-diynes (HC⋮CCH2)2X) in the presence of NiCl2(PPh3)2, Zn, and PPh3 at 90 °C in toluene afforded [2+2+2] bicyclic hexadiene derivatives (X = C(CO2Me)2 (2a), C(CO2Et)2 (2b), C(COMe)2 (2c), CH2 (2d), O (2e), NSO2-p-C6H5CH3 (2f), C(SO2Ph)2 (2g), and (2h) in good yields. Spectral data for products 2a−h indicated that the cycloaddition of diynes to C60 occurs across a 6,6-ring junction on the fullerene. On the basis of the established chemistry of metal-mediated [2+2+2] cycloaddition, a mechanism is proposed to account for the present nickel-mediated reaction. All the hexadiene derivatives 2a−h in solution are readily oxidized by molecular oxygen in the presence of light at ambient temperature. The oxidation process of compound 2a in chloroform-d was monitored by 1H NMR spectroscopy, and the results showed that 2a first reacted w...
TL;DR: In this paper, two conformationally restricted chiral bicyclic thiazolium salts have been synthesized by a concise, high-yielding route, which are effective catalysts for the benzoin condensation.
TL;DR: In this paper, a four-component, two-step, one-pot reaction between an aldehyde, a primary amine, an alkyl-β-(N,Ndimethylamino)-α-isocyanoacrylate and hydrazoic acid to form a substituted bicyclic tetrazole is disclosed.