Showing papers on "Bicyclic molecule published in 2003"

Synthesis and evaluation of 11c-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents

Abstract: The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 14 nM and 47 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition

Mechanism of the Alternating Copolymerization of Epoxides and CO2 Using β-Diiminate Zinc Catalysts: Evidence for a Bimetallic Epoxide Enchainment

Abstract: A series of zinc beta-diiminate (BDI) complexes and their solid-state structures, solution dynamics, and copolymerization behavior with CO(2) and cyclohexene oxide (CHO) are reported. Stoichiometric reactions of the copolymerization initiation steps show that zinc alkoxide and bis(trimethylsilyl)amido complexes insert CO(2), whereas zinc acetates react with CHO. [(BDI-2)ZnOMe](2) [(BDI-2) = 2-((2,6-diethylphenyl)amido)-4-((2,6-diethylphenyl)imino)-2-pentene] and (BDI-1)ZnO(i)Pr [(BDI-1) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)imino)-2-pentene] react with CO(2) to form [(BDI-2)Zn(mu-OMe)(mu,eta(2)-O(2)COMe)Zn(BDI-2)] and [(BDI-1)Zn(mu,eta(2)-O(2)CO(i)Pr)](2), respectively. (BDI-2)ZnN(SiMe(3))(2) inserts CO(2) and eliminates trimethylsilyl isocyanate to give [(BDI-2)Zn(mu-OSiMe(3))](2). [(BDI-7)Zn(mu-OAc)](2) [(BDI-7) = 3-cyano-2-((2,6-diethylphenyl)amido)-4-((2,6-diethylphenyl)imino)-2-pentene] reacts with 1.0 equiv of CHO to yield [(BDI-7)Zn(mu,eta(2)-OAc)(mu,eta(1)-OCyOAc)Zn(BDI-7)]. Under typical polymerization conditions, rate studies on the copolymerization exhibit no dependence in [CO(2)], a first-order dependence in [CHO], and orders in [Zn](tot) ranging from 1.0 to 1.8 for [(BDI)ZnOAc] complexes. The copolymerizations of CHO (1.98 M in toluene) and 300 psi CO(2) at 50 degrees C using [(BDI-1)ZnOAc] and [(BDI-2)ZnOAc] show orders in [Zn](tot) of 1.73 +/- 0.06 and 1.02 +/- 0.03, respectively. We propose that two zinc complexes are involved in the transition state of the epoxide ring-opening event.

Lewis acid-catalyzed benzannulation via unprecedented [4+2] cycloaddition of o-alkynyl(oxo)benzenes and enynals with alkynes.

Abstract: The reaction of o-alkynyl(oxo)benzenes 1 with alkynes 2 in the presence of a catalytic amount of AuCl3 in (CH2Cl)2 at 80 °C gave the [4+2] benzannulation products, naphthyl ketone derivatives 3 and 4, in high yields. When the reaction was carried out using AuBr3 instead of AuCl3, the reaction speed was enhanced and the chemical yield was increased. On the other hand, when the reaction was carried out in the presence of a catalytic amount of Cu(OTf)2 and 1 equiv of a Bronsted acid, such as CF2HCO2H, in (CH2Cl)2 at 100 °C, the decarbonylated naphthalene products 5 were obtained in high yields. Similarly, the Cu(OTf)2−H2O-promoted reaction of the enynals 7 with an alkyne 2 afforded the corresponding [4+2] benzannulation products, decarbonylated benzene derivatives 8, in good yields. Both AuX3- and Cu(OTf)2-catalyzed benzannulations proceed most probably through the formation of the benzo[c]pyrylium ate complex 10, the Diels−Alder addition of alkynes 2 to the ate complex, and the resulting bicyclic pyrylium i...

Ruthenium(II)-catalyzed selective intramolecular [2 + 2 + 2] alkyne cyclotrimerizations.

Abstract: In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes chemoselectively reacted with monoalkynes at ambient temperature to afford the desired bicyclic benzene derivatives in good yields. A wide variety of diynes and monoynes containing functional groups such as ester, ketone, nitrile, amine, alcohol, sulfide, etc. can be used for the present ruthenium catalysis. The most significant advantage of this protocol is that the cycloaddition of unsymmetrical 1,6-diynes with one internal alkyne moiety regioselectively gave rise to meta-substituted products with excellent regioselectivity. Completely intramolecular alkyne cyclotrimerization was also accomplished using triyne substrates to obtain tricyclic aromatic compounds fused with 5−7-membered rings. A ruthenabicycle complex relevant to these cyclotrimerizations was synthesized from Cp*RuCl(cod) and a 1,6-diyne possessing phenyl terminal groups, and its structure was unambiguously determined by X-ray analysis. The intermediary of such a ruthenacycle...

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.

Abstract: Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

Oxidation mechanism of aromatic peroxy and bicyclic radicals from OH-toluene reactions.

Abstract: Theoretical calculations have been performed to investigate mechanistic features of OH-initiated oxidation reactions of toluene. Aromatic peroxy radicals arising from initial OH and subsequent O(2) additions to the toluene ring are shown to cyclize to form bicyclic radicals rather than undergoing reaction with NO under atmospheric conditions. Isomerization of bicyclic radicals to more stable epoxide radicals possesses significantly higher barriers and, hence, has slower rates than O(2) addition to form bicyclic peroxy radicals. At each OH attachment site, only one isomeric pathway via the bicyclic peroxy radical is accessible to lead to ring cleavage. The study provides thermochemical and kinetic data for quantitative assessment of the photochemical production potential of ozone and formation of toxic products and secondary organic aerosol from toluene oxidation.

Asymmetric alternating copolymerization of cyclohexene oxide and CO2 with dimeric zinc complexes.

Abstract: Dimeric zinc complex 2a [ = Et2Zn2(1a)2] has been synthesized by the reaction of Et2Zn and (S)-diphenyl(pyrrolidin-2-yl)methanol (1a-H). X-ray crystallography revealed that the alkoxide ligand replaced one of the two ethyl groups of Et2Zn and formed a five-membered chelate ring through a ZnN dative bond. Two zinc centers were bridged by oxygen atoms to form a Zn2O2 four-membered ring with a syn relationship between the two ethyl groups on the zinc centers. Dimeric zinc complex 2a was an active catalyst for asymmetric alternating copolymerization of cyclohexene oxide and CO2. An MALDI-TOF mass spectrum of the obtained copolymer showed that the copolymerization was initiated by the insertion of CO2 into Znalkoxide to give [(S)-diphenyl(pyrroridin-2-ly)methoxy][C(O)O(1,2-cyclohexylene)O]nH (copolymer I), including chiral ligand 1a as an initiating group. Complex 3a-OEt ( = EtZn(1a)2ZnOEt), in which an ethoxy group replaced one of the two ethyl groups in 2a, also polymerized cyclohexene oxide and CO2 with hig...

Formation of Unusual Iridabenzene and Metallanaphthalene Containing Electron-Withdrawing Substituents

Abstract: A new route to irida-aromatic derivatives which consists of the oxidation of bicyclic compounds has been disclosed. The iridanaphthalene 3 experiences hydrolytic cleavage of the Ir-carboxylate moiety regenerating the bicyclic structure 5, whereas treatment of 5 with ClC(O)CO2Me yields back the metalla-aromatic 3.

Lobatamide C: Total Synthesis, Stereochemical Assignment, Preparation of Simplified Analogues, and V-ATPase Inhibition Studies

Abstract: The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a β-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.

Application of a new bicyclic triaminophosphine ligand in Pd-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides, bromides, and iodides.

Abstract: The new bicyclic triaminophosphine ligand P(i-BuNCH2)3CMe (3) has been synthesized in three steps from commercially available materials and its efficacy in palladium-catalyzed reactions of aryl halides with an array of amines has been demonstrated. Electron-poor, electron-neutral, and electron-rich aryl bromides, chlorides, and iodides participated in the process. The reactions encompassed aromatic amines (primary or secondary) and secondary amines (cyclic or acyclic). It has also been shown that the weak base Cs2CO3 can be employed with ligand 3, allowing a variety of functionalized substrates (e.g., those containing esters and nitro groups) to be utilized in our amination protocols. This ligand provides a remarkably general, efficient, and mild palladium catalyst for aryl iodide amination. Although 3 is slightly air and moisture sensitive, easy procedures can be adopted that avoid the need of a glovebox. Comparisons of the efficacy of 3 in these reactions with that of the proazaphosphatrane P(i-BuNCH2CH...

Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.

Abstract: Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65−84%, while observed regioselectivities were ≥90:10 for 1,8-naphthyridines and ≥84:16 for quinolines.

New Mechanistic Insights into the Iridium–Phosphanooxazoline-Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study

Abstract: This thesis describes mechanistic studies, rational ligand design, and synthesis of asymmetric transition metal catalysts. The topics addressed concerned [Papers I-VII]:[I] The asymmetric addition of diethyl zinc to N-(diphenylphosphinoyl)benzalimine catalyzed by bicyclic 2-azanorbornyl-3-methanols was studied. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center was developed, in the best case 97% ee was obtained with these ligands. The experimental results were rationalized by a computational DFT-study.[II] An aza-Diels-Alder reaction of cyclopentadiene with chiral heterocyclic imines derived from (S)-1-phenylethylamine and different heteroaromatic aldehydes was developed. The cycloaddition proved to be highly diastereoselective and offers a very rapid access to possible biologically active compounds and interesting precursors for chiral (P,N)-ligands. [III] A convenient and high-yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantio-enriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. [IV] The reaction mechanism of the iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins has been studied by means of DFT-calculations (B3LYP) and kinetic experiments. The calculations suggest that the reaction involves an unexpected IrIII-IrV catalytic cycle facilitated by coordination of a second equivalent of dihydrogen. On the basis of the proposed catalytic cycle, calculations were performed on a full system with 88 atoms. These calculations were also used to explain the enantioselectivity displayed by the catalyst.[V and VI] A new class of chiral (P,N)-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes was developed. These new ligands proved to be highly efficient and tolerate a broad range of substrates. The enantiomeric excesses are, so far, the best reported and can be rationalized using the proposed selectivity model.[VII] The complex formed between the quincorine-amine, containing both a primary and a quinuclidine amino function, and [Cp*RuCl]4 catalyzes the hydrogenation of aromatic and aliphatic ketones in up to 90% ee approx. 24-times faster than previously reported Ru-diamine complexes. The reason for the lower but opposite stereoselectivity seen with the quincoridine-amine, as compared to the quincorine-amine, was rationalized by a kinetic and computational study of the mechanism. The theoretical calculations also revealed a significantly lower activation barrier for the alcohol mediated split of dihydrogen, as compared to the non-alchol mediated process. A finding of importance also for the diphosphine/diamine mediated enantioselective hydrogenation of ketones.

Synthesis and antiviral activity of novel erythrofuranosyl imidazo[1,2-a]pyridine C-nucleosides constructed via palladium coupling of iodoimidazo[1,2-a]pyridines and dihydrofuran.

Abstract: 2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo[1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80−90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-d/l-erythrofuranosyl)imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix α gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the α-d anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most...

Origin of the synchronicity on the transition structures of polar Diels-Alder reactions. Are these reactions [4 + 2] processes?

Abstract: The transition structures (TSs) for a series of related Diels−Alder reactions between cyclopentadiene and mono-, di-, tri-, and tetracyanoethylene derivatives have been studied with use of DFT meth...

An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide bond rotation barrier in solution.

Abstract: Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution. A good correlation was found between the magnitudes of the rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett's σp+ constants, and this is consistent with the similarity of the solution structures. Calculations with the density functional theory reproduced the nitrogen-pyramidal structures of ...

Guanidinium receptors as enantioselective amino acid membrane carriers.

Abstract: A number of artificial carriers for the transport of zwitterionic aromatic amino acids across bulk model membranes (U-tube type) have been prepared and evaluated. 1,2-Dichloroethane and dichloromethane were employed in the organic phase. All compounds are based on a bicyclic chiral guanidinium scaffold that ideally complements the carboxylate function. The guanidinium central moiety was attached to crown ethers or lasalocid A as specific subunits for ammonium recognition as well as to aromatic or hydrophobic residues to evaluate their potential interaction with the side chains of the guest amino acids. The subunits were linked to the guanidinium through ester or amide connectors. Amides were found to be better carriers than esters, though less enantioselective. On the other hand, crown ethers were superior to lasalocid derivatives. As expected, transport rates were dependent on the carrier concentration in the liquid membrane. Reciprocally, enantioselectivities were much higher at lower carrier concentrations. The results show that our previously proposed three-point binding model (J. Am. Chem. Soc. 1992, 114, 1511-1512), involving the participation of the aromatic or hydrophobic residue to interact with the side chains of the amino acid guest, is unnecessary to explain the high enantioselectivities observed. Molecular dynamics fully support a two-point model involving only the guanidinium and crown ether moieties. These molecules constitute the first examples of chiral selectors for underivatized amino acids acting as carriers under neutral conditions.

Catalytic diastereoselective synthesis of diquinanes from acyclic precursors.

Abstract: Upon exposure of up to 10 mol % tributylphosphine, electron-deficient 1,7-enynes undergo [3 + 2] cycloaddition to afford bicyclo[3:3:0] ring systems. In all but one case, products were obtained in >95:5 de, as determined by 1H NMR. This methodology enables concise and diastereoselective access to diquinane ring systems, whereby three contiguous stereogenic centers are set in a single manipulation.

Bridged bicyclic cores containing a 1,1-diarylethylene motif are high-affinity subtype-selective ligands for the estrogen receptor.

Abstract: The actions of estrogens are mediated through the two estrogen receptors, ERalpha and ERbeta. Compounds that interact selectively with ERalpha or ERbeta are of interest because they could be used to explore the biological roles of these ER subtypes and they might be interesting estrogen pharmaceuticals. In a new approach to develop ER subtype-selective ligands, we have embellished the 1,1-diarylethylene motif, common to many nonsteroidal estrogens, with various bridged bicyclic or tricyclic cores, including ones based on bicyclo[3.3.1]nonane, bicyclo[2.2.1]heptane, and selected bi- and tricyclic terpenoids. This design leads to three-dimensional ER ligands of unusual structure that we have used to probe the size and shape of the ligand binding pocket of ERalpha and ERbeta. Many of these compounds have high binding affinities, with the best having a bicyclo[3.3.1]nonane core and binding 3-5 times better than estradiol to both ER subtypes. Some of the compounds show significant affinity selectivity in favor of ERbeta (4- to 5-fold), and in cell-based assays for transcriptional activity most are partial agonists on ERalpha and full antagonists on ERbeta.

Characterization of a colorless anthocyanin-flavan-3-ol dimer containing both carbon-carbon and ether interflavanoid linkages by NMR and mass spectrometry.

Abstract: Direct addition of anthocyanins and flavan-3-ols was investigated in a model system by incubating malvidin 3-glucoside and (-)-epicatechin in ethanol. Analysis of reaction products by high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC/ESI-MS) before and after thiolysis showed the formation of colorless dimers detected at m/z 781 in the negative ion mode, with retention times and spectroscopic characteristics identical to those of compounds detected in wine, which contain one malvidin 3-glucoside unit and one flavanol unit. On the basis of their resistance to thiolysis, these compounds were postulated to be bicyclic dimers linked with both carbon-carbon and ether bonds as observed in the case of A type proanthocyanidins. The major dimer analyzed by NMR experiments was identified as malvidin 3-glucoside(C2-O-C7,C4-C8)epicatechin, confirming this hypothesis. A similar assay was performed with (+)-catechin instead of (-)-epicatechin, and the formation of bicyclic dimers was also observed.

Intramolecular hydrogen abstraction reaction promoted by N-radicals in carbohydrates. Synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems.

Abstract: The reaction of phenyl and benzyl amidophosphates and alkyl and benzyl carbamate derivatives of aminoalditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems under neutral conditions. This reaction can be considered to be an intramolecular N-glycosidation that goes through an intramolecular 1,5-hydrogen abstraction promoted by an N-amido radical followed by oxidation of the transient C-radical intermediate to an oxycarbenium ion. This methodology proved to be useful not only as a suitable strategy for the preparation of these bicyclic arrays but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected N,O-uloses.

Fused bicyclic nitrogen-containing heterocycles

Abstract: Compounds, pharmaceutical compositions and methods that are useful in the treatment or prevention of metabolic and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the activity of proteins involved in lipid metabolism and cell proliferation.

Nucleophilic additions to fused bicyclic five-membered ring oxocarbenium ions: evidence for preferential attack on the inside face.

Abstract: Evidence is provided that nucleophilic attack on five-membered ring oxocarbenium ions occurs from the inside face of the envelope. An eight-five fused-bicyclic system in which two substituents are constrained to pseudoequatorial positions underwent nucleophilic addition with selectivity that was comparable to an unconstrained monocyclic system. On the other hand, a bicyclic six-five analogue underwent reaction with low selectivity. This observation indicates that minimization of eclipsing interactions by attacking inside the envelope is not enough to control selectivity, but that the changes in the overall three-dimensional structure of the ring must be favorable as well. In the bicyclic six-five series, the six-membered ring is accommodated in the cation, but it destabilizes the transition state structure leading to the first-formed product of inside attack.