Photochemistry of 2,2-Dimethyl-2H-Furo[3,4-b]Pyran-4,7(3H, 5H)-Dione

Irradiation (λ > 340 nm) of the title compound 2a in t-BuOH affords 3,3,10,10-tetramethyl-2,8-dioxatricyclo-[4.3.2.0^1,6]undecane-5,9-dione (3) via photoextrusion of 2-methylpropene and subsequent photocycloaddition of 2a to the alkene. The same regioisomer 3 is formed selectively and in much higher yields on irradiating 2a in the presence of excess 2-methylpropene. Irradiation of 3 (λ = 300 nm) in t-BuOH in the presence of the same alkene gives a 6:1 mixture of spirooxetanes 7a and 7b but not α-cleavage products. In 2-propanol, 2a is photoreduced to a 2:1 mixture of diastereoisomeric hydrodimers 9 .     

Mechanism of the diphenyldisulfone-catalyzed isomerization of alkenes. Origin of the chemoselectivity: experimental and quantum chemistry studies

Polysulfone- and diphenyldisulfone-catalyzed alkene isomerizations are much faster for 2-alkyl-1-alkenes than for linear, terminal alkenes. The mechanism of these reactions has been investigated experimentally for the isomerization of methylidenecyclopentane into 1-methylcyclopentene, and theoretically [CCSD(T)/6-311++G(d,p)//B3LYP/6-311++G(d,p) calculations] for the reactions of propene and 2-methylpropene with a methanesulfonyl radical, MeSO2*. On heating, polysulfones and (PhSO2)2 equilibrate with sulfonyl radicals, RSO2*. The latter abstract allylic hydrogen atoms in one-step processes giving allylic radical/RSO2H pairs that recombine within the solvent cage producing the corresponding isomerized alkene and RSO2*. The sulfinic acid, RSO2H, can diffuse out from the solvent cage (H/D exchange with MeOD,D2O) and reduce an allyl radical. Calculations did not support other possible mechanisms such as hydrogen exchange between alkenes, electron transfer, or addition/elimination process. Kinetic deuterium isotopic effects measured for the (PhSO2)2-catalyzed isomerization of methylidenecyclopentane and deuterated analogues and calculated for the H abstraction from 2-methylpropene and deuterated analogues by CH3SO2* are consistent also with the one-step hydrogen transfer mechanism. The high chemoselectivity for this reaction is not governed by an exothermicity difference but by a difference in ionization energies of the alkenes. Calculations for CH3SO2* + propene and CH3SO2* + 2-methylpropene show a charge transfer of 0.34 and 0.38 electron, respectively, from the alkenes to the sulfonyl radical in the transition states of these hydrogen abstractions.     

Screening for benfluorex and its major urinary metabolites in routine doping controls

Benfluorex [1-(m-trifluoromethylphenyl)-2-(β-benzoyloxyethyl)aminopropane] has been widely used for the treatment of atherogenic metabolic disorders and impaired carbohydrate metabolism (particularly in obese type-II diabetic patients) as well as an anorectic drug. Due to its potentially performance-enhancing properties, benfluorex has been added to the list of prohibited compounds and methods of doping by the World Anti-Doping Agency (WADA) in 2010, necessitating the implementation of the drug as well as its major metabolites into routine doping control procedures. In the present study, human urinary metabolites of benfluorex were characterized by gas chromatography–electron ionization–mass spectrometry (GC-EI-MS) as well as liquid chromatography–electrospray ionization–high resolution/high accuracy tandem mass spectrometry (LC-ESI-MS/MS). Commonly employed sports drug testing approaches consisting of liquid–liquid extraction followed by GC-MS or urine dilution and immediate LC-MS/MS analysis were expanded and validated with regard to specificity, recovery (48–54%, GC-MS only), intra- and interday precision (<25%), limits of detection (5–8 ng/mL for LC-MS/MS and 80 ng/mL for GC-MS), and ion suppression (for LC-ESI-MS/MS only) to allow the detection of benfluorex metabolites 1-(m-trifluoromethylphenyl)-2-(2-hydroxyethyl)aminopropane (M1), 1-(m-trifluoromethylphenyl)-2-(2-carboxymethyl)aminopropane (M2), and 1-(m-trifluoromethylphenyl)-2-aminopropane (M3) as well as the glucuronic acid conjugate of M1.     

Light-Induced Synthesis of Tricyclic Thiolane Derivatives from 2(5H)-thiophenones via consecutive radical ring closure

Two α,β-unsaturated thiolactones, 5-(2-propynyl)-2(5H)-thiophenone (5) and 3,5-di(2-propenyl)?2(5H)-thiophenone (6) , were newly synthesized. Irradiation (λ = 300 nm) of 5 in MeOH containing cyclopentene afforded a 3:1 mixture of diasteroisomeric methyl 7-thiatricyclo[6.4.0.0^2,6]dodec-10-ene-12-carboxylates (8a/8b) , while irradiation of 6 in MeOH saturated with 2-methylpropene gives a 3:2 mixture of diastereoisomeric methyl 3,3,9-trimethyl-5-thiatricyclo[6.2.1.0^2,6]undecane-1-carboxylates ( 10a / 10b ).     

Electronic tuning of the PNNP ligand for the asymmetric cyclopropanation of olefins catalysed by [RuCl(PNNP)]+

Cationic ruthenium complexes of the type [RuCl(L)(PNNP)]⁺ (L=OEt₂, OH₂), where PNNP is the CF₃-subsituted PNNP ligand N,N′-bis[o-(bis(4-trifluoromethylphenyl)phosphino)benzylidene]-(1S,2S)-diaminocyclohexane 1b, catalyse the asymmetric cyclopropanation of styrene, α-Me-styrene, and 1-octene with ethyl diazoacetate. These complexes are more active and give higher cis- and enantioselectivities than their analogues containing the unsubstituted ligand 1a. Thus, [RuCl(OEt₂)(1b)]PF₆ cyclopropanates α-Me-styrene with 85% cis selectivity and 86% ee in 94% isolated yield.     

流动相组成和温度对衍生化b-环糊精键合固定相拆 分四种仲醇消旋体的影响

采用3,5-二甲苯基异氰酸酯衍生化β-环糊精键合固定相, 以正己烷-脂肪醇为流动相, 研究了脂肪醇结构及其浓度、柱温对2-苯基环己醇、2-萘基环己醇、4-三氟甲基-2-苯基环己醇以及3-(1-羟乙基)香豆素等四种仲醇手性拆分行为的影响. 当流动相中醇的摩尔浓度相同时, 异构体容量因子随脂肪醇碳链的增长而减小; 柱温升高, 异构体容量因子减小, 而分离因子增大. 用溶质的计量置换保留模型(SDM-R)和热力学理论对此现象进行了解释.     

Spectroscopic evidence for the intermediacy of a 6-R-2,4-diazabicyclo-[3.1.0]hex-2-(3)ene in the photoisomerization of 4-R-1,4-(3,4)-dihydropyrimidines

¹H- and ¹³C-nmr spectroscopy is presented showing that photolysis of 4-(p-trifluoromethylphenyl)-1,4-(3,4)-dihydropyrimidine yields 6-(p-trifluoromethylphenyl)-2,4-diazabicyclo[3.1.0]hex-2-(3)ene.     

Preparation of Lewis acid ionic liquids for one-pot synthesis of benzofuranol from pyrocatechol and 3-chloro-2-methylpropene

Several Lewis acid ionic liquids (LAILs) with different acidic scales were synthesised and used as catalysts for the synthesis of benzofuranol by condensation of pyrocatechol and 3-chloro-2-methylpropene in one pot. The catalytic activity of these ionic liquids was correlated with their Lewis acidity. Low to moderate conversion with excellent selectivity to benzofuranol was obtained in the presence of the appropriate LAILs. Compared to the two-step synthetic method currently used in industry, a higher yield plateau (81.1%) of benzofuranol was achieved in the presence of [BMIm][AlCl₄] IL as catalyst at 418 K after 4 h. Furthermore, the catalyst is readily separated from the resultant products via decantation and could be reused after treatment in vacuum.     

The synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid: a precursor for cilastatin

S-(+)-2,2-Dimethylcyclopropane carboxylic acid, a precursor for cilastatin, was prepared from 2-methylpropene and chiral iron carbene in three steps. Asymmetric cyclopropanation reaction of 2-methylpropene with iron carbene complex having chirality at the carbene ligand, followed by exhaustive ozonolysis, produced S-(+)-2,2-dimethylcyclopropanecarboxylic acid of up to 92% ee. The absolute configuration of complexed chiral cyclopropane (−)-8 was determined by X-ray crystallographic analysis.     

Substitution reactions of 5-nitropyridine-2-sulfonic acid. A new pathway to 2,5-disubstituted pyridines

We have investigated reactions of 5-nitropyridine-2-sulfonic acid and its potassium salt in which substitution of the sulfonate group by oxygen, nitrogen and halogen nucleophiles has been attempted. By this approach, 2-methoxy- (95% yield), 2-ethoxy- (97%), 2-isopropoxy- (65%), 2-amino- (92%), 2-butylamino- (76%), 2-diethylamino- (62%), 2-ethylamino- (32%), 2-benzylamino- (77%), 2-(R-1-phenylethylamino)- (71%) and 2-chloro-5-nitropyridine (87%) have been obtained. No reactions were observed with phenols or anilines. With t-BuOH, 2-hydroxy-5-nitropyridine was formed together with 2-methylpropene.     

Preparation of fluoroalkylated benzoheterocycles using F-2-methylpropene

Several benzoheterocyclic compounds carrying a CH(CF₃)₂ group were prepared by the reactions of $\text{F}$-2-methylpropene with ortho-bifunctional benzenes. The reactivity and reaction mode of $\text{F}$-2-methylpropene in these reactions were compared with those of $\text{F}$-propene.     

Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

Summary Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxylate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within ± 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca²⁺ channel and its ability to accommodate both antagonist and activator ligands.     

Synthesis of a tritium-labeled, fipronil-based, highly potent, photoaffinity probe for the GABA receptor

3-[4-[1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazolo]]-3-(trifluoromethyl)diazirine is a fipronil-based (i.e. fiprole), high-affinity probe for the GABA receptor. For synthesis of the tritium-labeled version of this trifluoromethyldiazirinylfiprole ([(3)H]TDF) the required intermediate, 3-[4-[1-(2,6-dichloro-3-iodo-4-trifluoromethylphenyl)-5-iodopyrazolo]]-3-(trifluoromethyl)diazirine, was prepared in 10 steps from pyrazole and 3,5-dichloro-4-fluorobenzotrifluoride. One of the key transformations was lithiation and subsequent iodination of the 4-(2,2,2-trifluoro-1-hydroxyethyl)pyrazole intermediate. The last step involved reduction of the diiodofiprole with tritium, Pd/C, and triethylamine in ethyl acetate and afforded [(3)H]TDF with a specific activity of 15 Ci/mmol and 99% radiopurity.     

Photochemistry of 2-(Trifluoromethyl) cyclohexanone

The photochemical behaviour of the title compound 1a is compared to that of the non-fluorinated parent ketone 2-methylcyclohexanone ( 1b ). Substitution of the CH₃- group on C(2) by a trifluoromethyl group strongly enhances 2H- and RH- reduction product formation in cyclohexane or 2-propanol and oxetane formation in the presence of 2-methylpropene as olefinic component. Under all these conditions 1b exclusively undergoes a-cleavage, a process observed for 1a only in non-reducing solvents as benzene or tert-butyl alcohol.     

Studies on characterization, telomerase inhibitory properties and G-quadruplex binding of η6-arene ruthenium complexes with 1,10-phenanthroline-derived ligands

Two arene ruthenium complexes [Ru(η(6)-C(6)H(6))(p-MOPIP)Cl](+)1 and [Ru(η(6)-C(6)H(6))(p-CFPIP)Cl](+)2, where p-MOPIP = 2-(4-methoxyphenyl)-imidazo[4,5f][1,10] phenanthroline and p-CFPIP = 2-(4-trifluoromethylphenyl)-imidazo[4,5f][1,10] phenanthroline, were prepared and the interactions of these compounds with DNA oligomers 5'-G3(T2AG3)3-3'(HTG21) have been studied by UV-vis and circular dichroism (CD) spectroscopy, gel mobility shift assay, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay and telomeric repeat amplification protocol (TRAP) assay. The results show that both complexes can induce the stabilization of quadruplex DNA but complex 1 is a better G-quadruplex binder than complex 2. The two ruthenium complexes tested led to an inhibition of the enzyme telomerase and complex 1 was the significantly better inhibitor. A novel visual method has been developed for making a distinction between G-quadruplex DNA and double DNA by our Ru complexes binding hemin to form the hemin-G-quadruplex DNAzyme. Furthermore, in vitro cytotoxicity studies showed complex 1 exhibited quite potent antitumor activities and the greatest inhibitory selectivity against cancer cell lines.     

A Multi-Component Solvent System for the Analysis of a Candidate Antimalarial by Normal Phase HPLC

Abstract

The new candidate antimalarial WR 180,409·H₃PO₄ (DL-threo-α-(2-piperidyl)-2-trifluoromethyl-6-(4-trifluoromethylphenyl)-4-pyridinemethanol phosphate) and its internal standard, WR 184,806·H₃PO₄ (DL-2,8-bis(trifluoromethyl)-4-[1-hydroxy-3-(N-t-butylamino)propyl]-quinoline phosphate) are both hydrophobic, highly lipid soluble compounds. Organic extracts of biological fluids of these compounds can be separated and analyzed by normal phase systems. These organic extracts can be chromatographed by means of a Waters μ Bondapak CN column utilizing an organic solvent system composed of two major components (ethylene dichloride and hexane), one minor component (acetonitrile) and two trace modifiers (formic acid and water). Alterations in the proportions of the major components induce predictable shifts in the retention of the antimalarial and its internal standard, while alterations in the proportions of the minor component with respect to these major components induce predictable changes in column selectivity. If the trace modifiers are stabilized in proportionate amounts, proper concentrations of the major components will isolate the antimalarial and internal standard fraction from significant interference while simultaneous alteration of the amount of minor component will effect separation of the antimalarial from the internal standards.     

Role of photolysis frequency in enhanced selectivity and yield for controlled bond breaking in HOD

Quantum dynamical calculations on HOD subjected to different combinations of IR and UV pulses have been made to isolate field attributes which maximize selectivity and yield in the photodissociation of the desired O-H/O-D bond. Results from IR/UV pulse combinations which provide very high selectivity and/or yield are analyzed in detail by using population transfer, probability density flow, and flux variations to obtain microdynamic details favoring selectivity and yield. Results indicate that a 2727 cm (-1) 50 fs Gaussian IR pulse in conjunction with a 46,062 cm (-1) 50 fs Gaussian UV pulse with a time lag of approximately 90 fs between the IR and UV pulses gives 79.1% flux in the H-O + D channel and 6.6% flux in the H + O-D channel, whereas a 3706 cm (-1) 50 fs IR pulse in conjunction with a 51 090 cm (-1) UV pulse gives 9.2% flux in the H-O + D channel and 82.1% flux in the H + O-D channel. A 2727 cm (-1) 50 fs IR pulse in conjunction with a 40,062 cm (-1) 50 fs UV pulse provides the greatest selectivity among the sampled field profiles with a flux branching ratio of H-O + D/H + O-D approximately 487.8, and a 3706 cm (-1) 50 fs IR pulse in conjunction with a 45090 cm (-1) 50 fs UV pulse achieves a flux branching ratio of H + O-D/H-O + D approximately 1354.8.     

Heterodimerization of olefins. 1. Hydrovinylation reactions of olefins that are amenable to asymmetric catalysis

Through a systematic examination of ligand and counterion effects, new protocols for a nearly quantitative and highly selective codimerization of ethylene and various functionalized vinylarenes have been discovered. In a typical reaction, 4-bromostyrene and ethylene undergo codimerization in the presence of 0.0035 equiv each of [(allyl)NiBr]2, triphenylphosphine, and AgOTf in CH2Cl2 at -56 degrees C to give 3-(4-bromophenyl)-1-butene in >98% yield and selectivity. Corresponding reactions with [(allyl)PdX]2 are much less efficient and less selective and may require further optimization before a viable system can be identified. Another useful protocol that gives comparable yield and selectivity involves the use of a single-component catalyst prepared from allyl 2-diphenylphosphinobenzoate, Ni(COD)2, and (C6F5)3B. Recognition of a synergistic relationship between a chiral hemilabile ligand (for example, (R)-2-methoxy-2'-diphenylphosphino-1,1'-binaphthyl, MOP) and a highly dissociated counteranion (BARF or SbF6) in an enantioselective version of the Ni-catalyzed reaction raises the prospects of developing a practical route for the synthesis of 3-arylbutenes. Several pharmaceutically relevant compounds, including widely used 2-arylpropionic acids, can be synthesized from these key intermediates. This reaction appears to be quite general. Synthesis of several new 2-diphenylphosphino-1,1-binaphthyl derivatives, prepared to probe the effect of hemilabile coordination on the efficiency and selectivity of the reaction, are also described.     

Versatile diastereoselectivity in formal [3,3]-sigmatropic shifts of substituted 1-alkenyl-3-alkylidenecyclobutanols and their silyl ethers

A new method for the preparation of highly substituted cyclohexenones is reported. [2 + 2] Cycloaddition of 2-silyloxydienes with allenecarboxylate affords the 1-alkenyl-3-alkylidenecyclobutanol silyl ethers. Thermolysis of these compounds affords the methylene cyclohexenyl silyl ethers with excellent exo selectivity (>95:5) when monosubstituted alkenyl groups are used, while the use of disubstituted alkenyl groups gives generally low selectivity ( approximately 2:1). However, rearrangement of the anion of the cyclobutanol (prepared by acidic hydrolysis of the TMS silyl ether) at low temperature gives the endo product with good to excellent diastereoselectivity (5-23:1). Two different mechanistic rationales are given for the two different processes: the first via a diradical and the second via a cleavage intramolecular Michael addition. Thus, the same starting material (e.g., 20) can be converted into either the exo or endo product, 22x or 22n, with good diastereocontrol by just changing the rearrangement conditions.     

The Synthesis of Dilithio-Trimethylenemethane by Thermal Rearrangement of Monolithio-2-Methylpropene

Unsolvated dilithio-trimethylenemethane has been prepared by the thermal rearrangement of the two structural isomers, 1-lithio-2-methylpropene and 3-lithio-2-methylpropene. This further extends the Kawa-Lagow modified Ziegler rearrangement to olefinic systems.