An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes

On the basis of our Pd enolate chemistry, we have succeeded in developing an efficient catalytic enantioselective fluorination of β-ketophosphonates. In the presence of chiral Pd complexes 1 (1-10 mol %), various substrates including cyclic and acyclic β-ketophosphonates underwent the reaction with N-fluorobenzenesulfonimide (NFSI) in EtOH to give the corresponding fluorinated products in a highly enantioselective manner (94-98% ee).     

Resolution of β-unsaturated amines with isopropylidene glycerol hydrogen phthalate

1-Phenyl-2-propenylamine 2, 1-phenyl-2-propinylamine 3, 1-(1-cyclohexenyl)ethylamine 4, (E)-2-ethylidenecyclohexylamine 5 and α-methylallylamine hydrochloride 6 were selected as candidates for resolution with isopropylidene glycerol hydrogen phthalate 1, previously described as an efficient resolving agent of 1-arylalkylamines. With only the exception of 5, all these substrates were resolved by (S)-1. In particular both the enantiomers of 2 and 3 were obtained in excellent yields and with very high enantiomeric excesses. The absolute configurations of non-racemic forms of 2, 3 and 4, not prepared before except those of 3, were established by correlation with the respective hydrogenation products. The enantiomeric excesses of all the resolved substrates were accurately determined by chiral HPLC analysis. The fact that 1 resolves 4 and 6 but not their saturated analogues and shows higher efficiency in resolving 2 and 3 than 1-phenylpropylamine indicates the positive influence of the presence of β-unsaturation on the resolvability of aminic substrates with such an acid.     

Inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature

The ways for the practical preparation of stable inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature are developed. Mutual orientation of hydroxy groups and the nature of the bridge in the bisphenols are shown to affect considerably their ability to the complex formation.     

Diamagnetic lanthanide tris β-diketonate complexes with aryl-containing ligands as chiral NMR discriminating agents

Diamagnetic lanthanum(III) and lutetium(III) tris β-diketonate complexes with the aryl-containing ligands 3-benzoyl-(+)-camphor and 3-(2-naphthoyl)-(+)-camphor are effective organic-soluble chiral NMR discriminating agents for oxygen- and nitrogen-containing compounds. Enantiomeric discrimination of sufficient magnitude to determine the enantiomeric purity is observed in the ¹H NMR spectra of compounds with hydroxyl, carbonyl, oxazolidinone, amine, and sulfoxide groups. Diamagnetic lanthanide complexes with the aryl-containing β-diketonate ligands are almost always more effective than those with 3-trifluoroacetyl-(+)-camphor, 3-heptafluorobutyryl-(+)-camphor, and d,d-dicampholylmethane that have been previously reported. Many hydrogen atoms of the substrates are significantly shielded in the presence of the lanthanide chelates with the aryl-containing ligands, which likely enhances the extent of enantiomeric discrimination in the NMR spectra. No combination of metal and ligand is most effective for all substrates. Larger enantiomeric discrimination is usually observed in benzene-d₆ or cyclohexane-d₁₂ than in chloroform-d. Diamagnetic lanthanide tris β-diketonates with the aryl-containing ligands provide an alternative to paramagnetic chelates that often cause too much broadening in the ¹H NMR spectrum.     

Separation of chiral drugs with β-CD phosphate by capillary electrophoresis

In capillary electrophoresis (CE) chiral separation is accomplished by adding suitableselector in the running electrolyte"'. The type of selector is of primary importance forachieving successful resolution. Selector concentration has considerable influence aswell3'. Charged cyclodextrins were first introduced for chiral separation of aminoacidss and used for enantioseparation of drugs by Terabe group'. Many kinds ofcharged CDs are now commercially available7-11. The charged CD commonly use…     

Preparation and evaluation of inclusion complexes of diacerein with β-cyclodextrin and hydroxypropyl β-cyclodextrin

The objective of this research was to improve the aqueous solubility, dissolution rate and, consequently, bioavailability of diacerein, along with avoiding its side effect of diarrhea, by complexation with β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD). Phase solubility curve was classified as an A_N type for both the CDs, which indicated formation of complex of diacerein with β-CD and HP-β-CD in 1:1 stoichiometry and demonstrating that both CDs are proportionally less effective at higher concentrations. The complexes were prepared by kneading method and were evaluated to study the effect of complexation on aqueous solubility and rate of dissolution in phosphate buffer (pH 6.8). Based on the dissolution profile HP-β-CD was selected for preparing fast disintegrating tablet of diacerein which was compared with marketed formulation (MF-J). The HP-β-CD complex was probed for Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies which evidenced stable complex formation and increase in amorphousness of diacerein in complex. In brief, the characterization studies confirmed the inclusion of diacerein within the non-polar cavity of HP-β-CD. HP-β-CD complex showed improved in vitro drug release profile compared to pure drug and similar to that of marketed formulation respectively.     

Spectral properties and structures of supramolecular complexes of naphthylpyridine with β-cyclodextrin

The electronic absorption and fluorescence spectra of 4-(2-naphthyl)pyridine (1) and N-methyl-4-(2-naphthyl)pyridinium perchlorate (2 ⁺·ClO₄ ^–) were studied in aqueous solutions in the absence and presence of -cyclodextrin (-CD). In aqueous solutions and organic solvents in the presence of water or H⁺ ions, compound 1 exhibits intense fluorescence with a maximum at 21 270 cm^–1, and its quantum yield in an aqueous solution is 0.9±0.09. The same fluorescence spectrum was detected for an aqueous solution of 2 ⁺·ClO₄ ^–. In an aqueous solution, compound 1 and -CD form stable fluorescing supramolecular 2:2 complexes, whose structure was calculated by the quantum-chemical MNDO/PM3 method. The formation of these complexes induces a hypsochromic shift of the fluorescence maximum of 1 by 5000 cm^–1. The stability constant of the complex is 2·10³ L mol^–1. A decrease in the pH results in the formation of a protonated form of 1(1·H⁺) and destruction of the complex, thus favoring the escape of the substrate from the -CD cavity. The quantum-chemical calculations showed that the insertion of 1 into the -CD cavity is thermodynamically more favorable than hydration; on the contrary, the formation of 1·H⁺ increases dramatically the hydration energy, which promotes the escape of 1·H⁺ from the -CD cavity; cation 2 ⁺ does not form a complex with -CD; in the thermodynamically most favorable 2:2 complex, the naphthalene fragments of two molecules 1 are parallel to each other in a broad section of the -CD dimer constructed according to the head-to-head type.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2420–2425, November, 2004.     

Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges

Acetyl salicylic acid (ASA), a non-steroidal anti-inflammatory drug, was formulated into inclusion complexes by grinding and precipitation with β-cyclodextrin and freeze drying with pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin nanosponges. Particle size, zeta potential, encapsulation efficiency, accelerated stability study, in vitro and in vivo release studies were used as characterization parameters. TEM studies showed that the particle sizes of different inclusion complexes of ASA have diameters ranging from 40.12?±?8.79 to 59.53?±?15.55?nm. It also revealed the regular spherical shape and sizes of complexes that are even unaffected after drug encapsulation. Zeta potential was sufficiently high to obtain a stable colloidal formulation. The in vitro and in vivo studies indicated a slow and prolonged ASA release from PMDA cross-linked β-cyclodextrin nanosponges over a long period. XRPD, DSC and FTIR studies confirmed the interactions of ASA with nanosponges. XRPD showed the crystalline nature of ASA decreased after encapsulation. These results indicate that ASA nanosponges formulation can be used for oral delivery.     

Nonenzymatic kinetic resolution of racemic β-hydroxyalkanephosphonates with a chiral copper catalyst

Kinetic resolution of β-hydroxyalkanephosphonates was efficiently performed by 2-fluorobenzoylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst with good s value of up to 21.     

Thermodynamics of formation of β-cyclodextrin inclusion complexes with four series of surfactant homologs

We report on a titration microcalorimetric study of the formation of β-cyclodextrin inclusion complexes with the members of series of anionic, cationic, and nonionic surfactant homologs containing even numbers of carbon atoms in the alkyl chains. n-Alkyltrimethylammonium bromides (C_xTAB, x = 6–16), sodium n-alkyl sulfates (SC_xS, x = 6–12), sodium n-alkanesulfonates (SC_xSN, x = 6–12), and N,N-dimethylalkylamine-N-oxides (DC_xAO, x = 8–12) were selected for use. The stoichiometry, the binding constant, and the changes in enthalpy, entropy, and Gibbs free energy of the complexation reactions were determined at 298 K. It was found in each case that the complexation is favored by both the enthalpy and the entropy changes and that the thermodynamics of the process is affected far more strongly by the length of the alkyl chain than by the nature of the headgroup.     

Synthesis of axially chiral oxazoline–carbene coordinated palladium complexes with a N-phenyl framework

A family of tropos ligands bearing a N-heterocyclic carbene and a chiral oxazoline coordination group with a N-phenyl framework were easily prepared,and their coordination behavior with Pd(Ⅱ)acetate was performed,affording a series of axially chiral palladium complexes in good yields.     

Structure of guest-host complexes of β-cyclodextrin with arenes: a quantum-chemical study

The structure of β-cyclodextrin (β-CD), as well as the structure and energetics of β-CD-naphthalene, β-CD-fluorene, β-CD-phenanthrene, β-CD-cyclohexane (1:1), and β-CD-naphthalene (2:2) inclusion complexes was studied by the semiempirical MNDO/PM3 method. Calculations of a β-CD-naphthalene-cyclohexane (1:1:1) complex were also performed. The minimum heat of formation was found for the symmetric β-CD conformation withC ₇ symmetry axis. The structure is stabilized by the ring of interunit H-bonds formed by the protons of the 2-OH groups and the O atoms of the 3′-OH groups of the glucose units. Preferableness of this orientation of interunit H-bonds was confirmed byab initio calculations of the molecule of α-(1–4)-glucobiose (maltose) in the MP2/6-31G(d,p)//6-31G(d,p) approximation. The formation of any inclusion compounds of β-CD with arenes is energetically favorable: the complexation energy varies in the range −9 to −12 kcal mol⁻¹. Among complexes with naphthalene, that of composition 2:2 is the most energetically favorable, which is in agreement with experimental data. In this complex, β-CD exists as a dimer of the “head-to-head” type, in which both partners are linked by a system of H-bonds. The structure of the “head-to-head” dimer of β-CD was simulated byab initio calculations of the H-bonded dimer of α-d-glucose in the RHF/6-31G(d,p) approximation. In the dimer, both components are linked by a pair of H-bonds formed by the protons of the 3-OH groups and the O atoms of the, 2-OH groups. The dimerization energies obtained fromab initio and semiempirical MNDO/PM3 and AM1 calculations differ by about 2.5 times (8.6vs 3.2 and 3.8 kcal mol⁻¹, respectively).     

Synthesis and magnetooptical properties of mesomorphic complexes of lanthanides with β-aminovinyl ketones

Complexes of the composition L(LH)₂Ln(NO₃)₂ (Ln = La, Dy, Gd, Er, Eu, or Tb) were obtained by the reaction of -aminovinyl ketone (LH) with rare earth metal nitrates. All the compounds synthesized are thermotropic liquid crystals having the smectic S_A phase. The values of magnetic anisotropy of these complexes measured by magnetic birefringence are fairly high.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2331–2333, September, 1996.     

Synthesis of benzannulated spiroacetals using chiral gold–phosphine complexes and chiral anions

The development of an asymmetric gold-catalysed dihydroalkoxylation strategy for the synthesis of the 3′H-spiro[chroman-2,1′-isobenzofuran] spiroacetal ring system 5 is described. Spiroacetal was generated in up to 87:13 enantiomeric ratio using chiral gold–phosphine complexes and chiral silver phosphate Ag(S)-TRIP.     

Resolution of 1,3-alkanediols via chiral spiroketals derived from ℓ-menthone

Ketalization reaction of racemic 1,3-alkanediols with ℓ-menthone gave a mixture of diastereomeric spiroketals that was easily separated by silica gel column chromatography and converted into enantiomerically pure diols by acid-catalyzed hydrolysis.     

Catalytic enantioselective chlorination of cyclic β-keto esters in the presence of chiral Pd(II) complexes

The catalytic enantioselective electrophilic chlorination promoted by chiral palladium complexes is described. The treatment of β-keto esters with 2,3,4,5,6,6-hexachlorocyclohex-2,4-dienone as chlorine source under mild reaction conditions afforded the corresponding α-chlorinated β-keto esters with excellent enantioselectivities (up to 94% ee).     

Enantioselective formation of quaternary centers on β-ketoesters with chiral palladium QUIPHOS catalyst

Asymmetric formation of quaternary centers by allylic alkylation of β-ketoesters using the chiral palladium QUIPHOS catalyst has been achieved. The results obtained not only depend on the reaction conditions but also on the structural features of both β-ketoesters and allylating agents. Enantiomeric excesses of up to 95% have been observed.     

Theoretical study of β- and γ-cyclodextrin complexes with ferrocene-containing azoles

The interaction between cyclodextrins (β- and γ-CD) and ferrocenyl azoles (i.e., pyrazole ferrocenes (I, III–V) and benzimidazole ferrocenes (VI, VII)), along with 1-ferrocenylethanol (II), each in the form of (R)- and (S)-enantiomers, in forming inclusion complexes is studied for the first time using detailed quantum chemical calculations. Compounds are calculated in terms of the density functional theory (DFT), using the Becke–Lee–Yang–Parr (B3LYP) approach in the 6-31G* basis sets. For the considered CD complexes with enantiomers of I–VII, structures in which a guest partially enters a host cavity from the side of the heterocyclic substituent (pyrazole or benzimidazole) are found to be energetically advantageous. It is shown that for successful resolution of (R,S)-enantiomers on chiral phases containing cyclodextrins, we must consider the interaction between outer hydroxyl groups on the CD cone’s surface, in addition to the correspondence of geometric dimensions. The calculated data correlate well with the data from the chromatographic separation of guest enantiomers on cyclodextrin sorbents.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.