Low-valent niobium-catalyzed reduction of alpha,alpha,alpha-trifluorotoluenes

[reaction: see text] In the presence of 5 mol % of niobium(V) chloride, alpha,alpha,alpha-trifluorotoluene derivatives were reduced with lithium aluminum hydride to give toluene derivatives in good yields. Stepwise, partial reduction of bis(trifluoromethyl)benzene derivative was also demonstrated.     

Alpha,2-, alpha,3-, and alpha,4-dehydrophenol radical anions: formation,reactivity, and energetics leading to the heats of formation of alpha,2-, alpha,3-, and alpha,4-oxocyclohexadienylidene

We have regiospecifically generated the alpha,2-, alpha,3-, and alpha,4-dehydrophenoxide anions by collisional activation of o-, m-, and p-nitrobenzoate. The alpha,2 and alpha,4 isomers also were synthesized by reacting o-benzyne radical anion with carbon dioxide and electron ionization of p-diazophenol. All three dehydrophenol radical anions were differentiated from each other and identified by probing their chemical reactivity with several reagents. Each isomer was converted to phenoxide and its corresponding quinone as well. Thermochemical measurements were carried out on all three radical anions and their hydrogen-atom affinities, proton affinities, and electron binding energies are reported. These measured quantities are combined in thermodynamic cycles to derive the heats of formation of each of the radical anions and their corresponding carbenes (i.e., alpha,2-, alpha,3-, and alpha,4-dehydrophenol). These results are compared to MCQDPT2, G3, G2+(MP2), and B3LYP calculations and experimental data for appropriate reference compounds.     

GaCl3-catalyzed skeletal rearrangement of alpha,alpha,alpha-trisubstituted aldehydes

[Reaction: see text] GaCl3 is found to be a superior catalyst for the skeletal rearrangement of alpha,alpha,alpha-trisubstituted aldehydes to ketones. The rearrangement can proceed smoothly in the presence of a catalytic amount of GaCl3, and even substrates having no heteroatoms alpha to the carbonyl group or without steric strains can be used. Double activation of a carbonyl group by two molecules of GaCl3 was supported on the basis of experimental data and a DFT study.     

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.     

Potential bile acid metabolites. 25. Synthesis and chemical properties of stereoisomeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids

Epimeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids and some related compounds were synthesized from chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. The key reaction involved one-step remote oxyfunctionalization of unactivated methine carbons at C-17 of CDCA and at C-14 of UDCA as their methyl ester-peracetate derivatives with dimethyldioxirane (DMDO). After dehydration of the resulting 17alpha- and 14alpha-hydroxy derivatives with POCl(3) or conc. H(2)SO(4), the respective Delta(16)- and Delta(14)-unsaturated products were subjected to hydration via hydroboration followed by oxidation to yield the 3,7,16- and 3,7,15-triketones, respectively. Stereoselective reduction of the respective triketones with tert-butylamine-borane complex afforded the epimeric 3alpha,7alpha,16- or 3alpha,7alpha,15-trihydroxy derivatives exclusively. A facile formation of the corresponding epsilon-lactones between the side chain carboxyl group at C-24 and the 16alpha- (or 16beta-) hydroxyl group in bile acids is also clarified.     

Organocatalytic and direct asymmetric vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes

The first highly regio-, chemo-, diastereo- and enantioselective direct vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes is described, employing readily available chiral alpha,alpha-diarylprolinol salts as iminium organocatalysts.     

Aromatic chlorination of omega-phenylalkylamines and omega-phenylalkylamides in carbon tetrachloride and alpha,alpha,alpha-trifluorotoluene

The aromatic halogenation of simple alkylbenzenes with chlorine proceeds smoothly in acetic acid but is much less efficient in less polar solvents. By contrast chlorination of omega-phenylalkylamines, such as 3-phenylpropylamine, occurs readily in either acetic acid, carbon tetrachloride or alpha,alpha,alpha-trifluorotoluene, and in the latter solvents gives high proportions of ortho-chlorinated products. These effects are attributable to the involvement of N-chloroamines as reaction intermediates, with intramolecular delivery of the chlorine electrophile. Omega-phenylalkylamides, such as 3-phenylpropionamide, also easily undergo aromatic chlorination in carbon tetrachloride and alpha,alpha,alpha-trifluorotoluene. These reactions generally show a first-order dependence on the substrate concentration, but not on the amount of chlorine. With carbon tetrachloride, very similar reaction rates are observed with chlorine concentrations ranging from 0.1-1.5 M. In alpha,alpha,alpha-trifluorotoluene, the rates reach a plateau at a chlorine concentration of approximately 0.2 M. These features indicate that the reactions proceed via the formation of intermediates which evidence suggests may be the corresponding O-chloroimidates. Irrespective of the mechanistic details, the reactions are remarkably rapid, being faster than analogous reactions in acetic acid and three to four orders of magnitude more rapid than reactions of simple alkylbenzenes in carbon tetrachloride. Therefore, chlorination of the amines and amides may be accomplished without the need for highly polar solvents, added catalysts or large excesses of chlorine, which are often employed for electrophilic aromatic substitutions. Although the use of carbon tetrachloride is becoming increasingly impractical due to environmental concerns, the trifluorotoluene is a suitable alternative.     

Enantioselective epoxidation of alpha,beta-enones promoted by alpha,alpha-diphenyl-L-prolinol as bifunctional organocatalyst

[reaction: see text] An operationally simple and mild protocol for the catalytic enantioselective epoxidation of alpha,beta-unsaturated ketones has been estabilished using commercially available alpha,alpha-diphenyl-l-prolinol as bifunctional organocatalyst and tert-butyl hydroperoxide (TBHP) as oxidant. The epoxides have been obtained in good yields and with up to 80% ee.     

Electron ionization mass spectral fragmentation of cholestane-3beta,4alpha,5alpha-triol and cholestane-3beta,5alpha,6alpha/beta-triol bis- and tris-trimethylsilyl derivatives

The electron ionization (EI) mass spectral fragmentation of the bis- and tris-trimethylsilyl derivatives of cholestane-3beta,4alpha,5alpha-triol, cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol was investigated. The EI mass spectrum of the 3beta,4alpha-bis-trimethylsilyl derivative of cholestane-3beta,4alpha,5alpha-triol exhibits interesting fragment ions at m/z 142 and 332 resulting from the initial loss of TMSOH between the carbons 2 and 3 and subsequent retro-Diels-Alder (RDA) cleavage of the ring A. Trimethylsilyl transfer between the 4alpha- and the 5alpha-hydroxy groups acts significantly before RDA cleavage affording an ion at m/z 404. Complete silylation of cholestane-3beta,4alpha,5alpha-triol strongly stabilizes the molecule, affording an abundant molecular ion at m/z 636 and decreasing the abundance of the RDA cleavage. Loss of water (from the non-silylated 5alpha-hydroxy group) plays a very important role during the decomposition of the molecular ion of 3beta,6alpha/beta-bis-trimethylsilyl derivatives of cholestane-3beta,5alpha,6alpha/beta-triols. These derivatives appear to be very useful in assigning the configuration of the carbon 6. This assignment is based on the abundance of the fragment ions at m/z 321, 367 and 403, which are more prominent in the EI mass spectrum of the beta-isomer. In contrast, EI mass spectra of the tris-trimethylsilyl derivatives of cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol differ only slightly and appear to be poorly informative.     

Synthesis of 6-hydroxylated bile acids and identification of 3 alpha,6 alpha,7 alpha,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid in human meconium and neonatal urine

Three 6-hydroxylated bile acids, 3 alpha,6 alpha,7 alpha,12 alpha-, 3 alpha,6 beta,7 alpha,12 alpha- and 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acids, were synthesized from methyl cholate, and a sensitive method was developed for analyzing them by gas chromatography-mass spectrometry for the stoichiometric study of fetal bile acids. 3 alpha,6 alpha,7 alpha,12 alpha-Tetrahydroxy-5 beta-cholan-24-oic acid (6 alpha-hydroxylated cholic acid) was identified from human meconium and healthy neonatal urine by comparison with the mass spectrum of the reference compound. In human meconium, 6 alpha-hydroxylated cholic and chenodeoxycholic acids were determined in 1.2% and 29.0% of the total bile acids, respectively. We discuss the significance of hydroxylation at the C-1 beta and C-6 alpha positions of bile acids and their elimination in fetal and neonatal periods.     

Asymmetric Lewis acid-catalyzed Diels-Alder reactions of alpha,beta-unsaturated ketones and alpha,beta-unsaturated acid chlorides

[reaction: see text] Conformational analysis, van der Waals attractions, and transition structure calculations are combined to design an asymmetric Lewis acid-catalyzed Diels-Alder reaction for simple acyclic alpha,beta-unsaturated ketones and alpha,beta-unsaturated acid chlorides, giving up to 83 and 92% ee, respectively. The two-point-binding chiral recognition mechanism, Lewis acid-Lewis base coordination with boron and a van der Waals attraction with the naphthyl group, uses the inherent enone unit of simple alpha,beta-unsaturated carbonyl compounds, ending the need for auxiliary oxygen binding sites on the dienophile.     

Intrinsic conformational preferences of C(alpha,alpha)-dibenzylglycine

The intrinsic conformational preferences of C (alpha,alpha)-dibenzylglycine, a symmetric alpha,alpha-dialkylated amino acid bearing two benzyl substituents on the alpha-carbon atom, have been determined using quantum chemical calculations at the B3LYP/6-31+G(d,p) level. A total of 46 minimum energy conformations were found for the N-acetyl- N'-methylamide derivative, even though only nine of them showed a relative energy lower than 5.0 kcal/mol. The latter involves C 7, C 5, and alpha' backbone conformations stabilized by intramolecular hydrogen bonds and/or N-H...pi interactions. Calculation of the conformational free energies in different environments (gas-phase, carbon tetrachloride, chloroform, methanol, and water solutions) indicates that four different minima (two C 5 and two C 7) are energetically accessible at room temperature in the gas phase, while in methanol and aqueous solutions one such minimum (C 5) becomes the only significant conformation. Comparison with results recently reported for C (alpha,alpha)-diphenylglycine indicates that substitution of phenyl side groups by benzyl enhances the conformational flexibility leading to (i) a reduction of the strain of the peptide backbone and (ii) alleviating the repulsive interactions between the pi electron density of the phenyl groups and the lone pairs of the carbonyl oxygen atoms.     

Catalytic asymmetric synthesis of alpha,alpha,alpha-trifluoromethylamines by the copper-catalyzed nucleophilic addition of diorganozinc reagents to imines

[reaction: see text] A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphinoylimines has been developed for the synthesis of chiral alpha,alpha,alpha-trifluoromethylamines. The trifluoromethyl ketimines, generated in situ from the corresponding hemiaminals, led to the chiral amides in high yields (71-89%) and excellent enantiocontrol (91-99% ee).     

Novel alpha,alpha-difluorohomophthalimides via copper-catalyzed tandom cross-coupling-cyclization of 2-halobenzamides with alpha,alpha-difluoro Reformatskii reagent

Novel alpha,alpha-difluorohomophthalimides 2 were prepared by reacting N-substituted 2-halobenzamides with the alpha,alpha-difluoro Reformatskii reagent BrZnCF2CO2Et (3) in the presence of CuBr at room temperature. The synthesis involves a CuBr-mediated cross-coupling of 3 with aryl iodides or activated aryl bromides, followed by a spontaneous cyclization of the ethyl 2-benzamido-alpha,alpha-difluoroacetate intermediates at room temperature. N-unsubstituted alpha,alpha-difluorohomophthalimides 2 (R' = H), bearing an acidic imide proton capable of acting as a carboxylic acid bioisostere, were also prepared by reacting 3 equiv of 3 with the parent 2-iodobenzamides. Other aryl iodides such as 3-iodo-imidazo[1,2-alpha]pyridine were also used for the tandem coupling-cyclization reaction.     

Enantioselective synthesis of alpha,beta-disubstituted-beta-amino acids

Highly diastereoselective and enantioselective addition of N-benzylhydroxylamine to imides 17 and 20-30 produces alpha,beta-trans-disubstituted N-benzylisoxazolidinones 19 and 31-41. These reactions proceed in 60-96% ee with 93-99% de's using 5 mol % of Mg(NTf2)2 and ligand 18. The product isoxazolidinones can be hydrogenolyzed directly to provide alpha,beta-disubstituted-beta-amino acids.     

Low-valent niobium-mediated double activation of C-F/C-H bonds: fluorene synthesis from o-arylated alpha,alpha,alpha-trifluorotoluene derivatives

By the treatment of 0.3 molar amount of NbCl5 and LiAlH4, o-arylated alpha,alpha,alpha-trifluorotoluenes afforded fluorene derivatives in good yields. C-F bonds of the CF3 group and the neighboring ortho C-H bond were doubly activated to give the coupling products.     

Synthesis of 5 beta-cholestane-3 alpha,6 beta,7 alpha,25,26-pentol and identification of a novel bile alcohol, alpha-trichechol, present in the West Indian manatee bile

In order to confirm the structure of alpha-trichechol, the major bile alcohol of the West Indian manatee, chemical synthesis of 5 beta-cholestane-3 alpha,6 beta,7 alpha,25,26-pentol was carried out. The chain of 3 alpha-hydroxy-5 beta-chol-6-en-24-oic acid was elongated by an Arndt-Eistert reaction to form 3 alpha-hydroxy-26,27-dinor-5 beta-cholest-6-en-25-oic acid. The unsaturated C25 bile acid was converted into 3 alpha,6 beta,7 alpha-trihydroxy-25-homo-5 beta-cholan-25-oic acid by 1,2-glycol formation of the delta 6-double bond. The acetylated derivative of the trihydroxy C25 bile acid was then converted into 3 alpha,6 beta,7 alpha,26-tetraacetoxy-27-nor-5 beta-cholestan-25-one by successive treatment with thionyl chloride, diazomethane, and acetic acid. A Grignard reaction of the 25-oxo compound with methylmagnesium iodide afforded the desired bile alcohol, 5 beta-cholestane-3 alpha,6 beta,7 alpha,25,26-pentol. By direct comparison with the synthetic pentahydroxy bile alcohol, the structure of the naturally occurring alpha-trichechol was determined to be 5 beta-cholestane-3 alpha,6 beta,7 alpha,25,26-pentol.     

Intrinsic conformational characteristics of alpha,alpha-diphenylglycine

Quantum mechanical calculations at the B3LYP/6-31+G(d,p) level have been used to investigate the intrinsic conformational preferences of alpha,alpha-diphenylglycine, a simple alpha,alpha-dialkylated amino acid bearing two phenyl substituents on the alpha-carbon, in both the gas phase and aqueous solution. Nine minimum energy conformations have been characterized for the N-acetyl-N'-methylamide derivative within a relative energy range of about 9 kcal/mol. The relative stability of these structures is largely influenced by specific backbone...side chain and side chain...side chain interactions that can be attractive (N-H...pi and C-H...pi) or repulsive (C=O...pi). On the other hand, comparison with the minimum energy conformations calculated for alpha-aminoisobutyric acid, in which the two phenyl substituents are replaced by methyl groups, revealed that the bulky aromatic rings of alpha,alpha-diphenylglycine induce strain in the internal geometry of the peptide. Finally, a set of force-field parameters for classical Molecular Mechanics calculations was developed for the investigated amino acid. Molecular Dynamics simulations in aqueous solutions have been carried out to validate the parameters obtained.     

First-row transition-metal complexes of a new pentadentate ligand, alpha,alpha,alpha',alpha'-tetra(pyrazolyl)lutidine

A new pentadentate ligand, alpha,alpha,alpha',alpha'-tetra(pyrazolyl)lutidine, pz 4lut, has been prepared by a CoCl 2-catalyzed rearrangement reaction between 2,6-pyridinedicarboxaldehyde and dipyrazolylthione. The coordination chemistry with some divalent first-row transition metal (Mn, Fe, Co, Ni, Cu, and Zn) chlorides has been explored. The electronic properties indicate that the new kappa (5)N ligand is a slightly stronger-field donor to Ni (2+) and Co (2+) than a related pentadentate ligand with five pyridyl donors presumably because of greater interaction between the metal and axial pyridyl.     

Determination of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha, thromboxane B2, 2,3-dinor-thromboxane B2, PGE2, PGD2 and PGF2 alpha in human urine by gas chromatography-negative ion chemical ionization mass spectrometry

A method for quantification of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha TXB2, 2,3-dinor TXB2, PGE2, PGD2 and PGF2 alpha in human urine samples, using gas chromatography-negative ion chemical ionization mass spectrometry, is described. Deuterated analogues were used as internal standards. Methoximation was carried out in urine samples which were subsequently applied to phenylboronic acid cartridges, reversed-phase cartridges and thin-layer chromatography. The eluents were further derivatized to pentafluorobenzyl ester trimethylsilyl ethers for final quantification by gas chromatography-mass spectrometry. The overall recovery was 77% for tritiated 6-keto-PGF1 alpha and 55% for tritiated TXB2. Urinary levels of prostanoids were determined in a group of six volunteers before and after intake of the thromboxane synthase inhibitor Ridogrel, and related to creatinine clearance.