Synthesis of various camphor-based chiral pyridine derivatives

(+)-β-Hydroxymethylenecamphor 1 and enamines 2a-e were transformed into chiral camphor-based pyridine derivatives 3a-e via a tandem condensation reaction in good yields.     

A new type of chiral porphyrin: Organopalladium porphyrins with chiral chelating diphosphine ligands

Peripherally palladated Ni(II) porphyrins have been prepared using enantiopure chiral chelating diphosphines as supporting ligands on the attached Pd(II) fragment. Both enantiomers of the following complexes have been obtained in good yields, using oxidative addition of the bromoporphyrin starting material 5-bromo-10,20-diphenylporphyrinatonickel(II) (NiDPPBr (1)) to the [Pd⁰L] complex generated in situ from Pd₂dba₃ and the chiral ligand L: [PdBr(NiDPP)(CHIRAPHOS)] (2a,b) [CHIRAPHOS = 2,3-bis(diphenylphosphino)butane], [PdBr(NiDPP)(Tol-BINAP)] (3a,b) [Tol-BINAP) = 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl] and [PdBr(NiDPP)(diphos)] [diphos = 1,2-bis(methylphenylphosphino)benzene] (4a,b). The induced asymmetry in the porphyrin was readily detected by ¹H NMR and CD spectroscopy. The porphyrin chiroptical properties are strongly dependent upon the structure of the chiral ligand, such that a monosignate CD signal, and symmetric and asymmetric exciton couplets were observed for 4a, 2b, and 3a,b, respectively.     

The investigation of stereogenic properties of cyclotriphosphazene derivatives with two different chiral centres

Hexachlorocyclotriphosphazene N₃P₃Cl₆ and gem-disubstituted cyclotriphosphazene derivatives N₃P₃Cl₄X₂ (X = Ph, PhS, PhNH) were reacted with N-methyl-1,3-propanediamine and 3-amino-1-propanol to give compounds (9a-12a, 9b-12b) which exist as cis and trans geometric isomers and are two different racemic isomers, respectively to describe the stereogenic properties of a series of chiral cyclotriphosphazene compounds with two different centres of chirality. The geometric isomers were separated by column chromatography on silica gel and analysed by elemental analysis, mass spectrometry, and ³¹P and ¹H NMR spectroscopies, and also the geometric forms (cis or trans) of 9b, 10a, 11a, 11b and 12a have been determined by the X-ray crystallography. The enantiomers of all racemic compounds have been analysed by the changes in ³¹P NMR spectra on addition of a Chiral Solvating Agent (CSA), (R)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol. On the other hand, the racemic forms of chiral cyclotriphosphazene derivatives have been confirmed by contribution of chiral HPLC methods which have been developed for this study.     

Cycloalkane-1,2-diamine derivatives as chiral solvating agents. Study of the structural variables controlling the NMR enantiodiscrimination of chiral carboxylic acids

A family of pincer-like receptors (2-5) has been synthesized and tested for the NMR enantiodiscrimination (CSA) of chiral carboxylic acids. Starting from a previous design (1), different structural variables have been mapped on the receptor frame. The splitting of the signals of the acids upon the addition of the CSAs largely depends on these structural variables. Thus, we concluded that the C₂ symmetrical pyridine-2,6-biscarboxamide moiety is a key structural feature for the efficiency of the CSA. Structural studies by NMR and molecular modeling showed that this moiety promotes the U-shape-folded pincer-like conformation by intramolecular H-bonds. On the other hand, we also observed that the cyclohexane-1,2-diamine derivative 5 is a more versatile CSA than its cyclopentane analogue 1, as 5 shows a better performance for more structurally different acids. However, the original cyclopentane derivative (1) remained the best for the arylpropionic acids. Finally, combination of NMR and modeling studies allowed us to propose a reasonable model for the interaction and, accordingly, for the observed NMR enantiodiscrimination.     

Rhodium complexes with chiral counterions: achiral catalysts in chiral matrices

The neutral complexes [Rh(I)(NBD)((1S)-10-camphorsulfonate)] (2) and [Rh(I)((R)-N-acetylphenylalanate)] (4) reacted with bis-(diphenylphosphino)ethane (dppe) to form the cationic Rh(I)(NBD)(dppe) complexes, 5 and 6, respectively, accompanied by their corresponding chiral counteranions. Analogously, 4 reacted with 4,4^′-dimethylbipyridine to yield complex 7. Complexes 5 and 6 disproportionated in aprotic solvents to form the corresponding bis-diphosphine complexes 8 and 9, respectively. 8 was characterized by an X-ray crystal structure analysis. In order to form achiral Rh(I) complexes bearing chiral countercations new sulfonated monophosphines 13-16 with chiral ammonium cations were synthesized. Tris-triphenylphosphinosulfonic acid (H₃TPPS, 11) was used to protonate chiral amines to yield chiral ammonium phosphines 14-16. Thallium-tris-triphenylphosphinosulfonate (Tl₃TPPS, 12) underwent metathesis with a chiral quartenary ammonium iodide to yield the proton free chiral ammonium phosphine 13. Phosphines 15 and 16 reacted with [Rh(NBD)₂]BF₄ to afford the highly charged chiral zwitterionic complexes [Rh(NBD)(TPPS)₂][(R)-N,N-dimethyl-1-(naphtyl)ethylammonium]₅ (17) and [Rh(NBD)(TPPS)₂][BF₄][(R)-N,N-dimethyl-phenethylammonium]₆ (18), respectively. Complexes 5, 6, and 18 were tested as precatalysts for the hydrogenation of de-hydro-N-acetylphenylalanine (19) and methyl-(Z)-(α)-acetoamidocinnamate (MAC, 20) under homogeneous and heterogeneous (silica-supported and self-supported) conditions. None of the reactions was enantioselective.     

Asymmetric addition of diethylzinc to aromatic aldehydes by chiral ferrocene-based catalysts

A series of chiral C₁- and C₂-symmetric ferrocenyl Schiff bases (1a-c), ferrocenyl aminoalcohols (2a), ferrocenylphosphinamides (2b-c), 1,1′-ferrocenyl-diol (3), and 1,1′-ferrocenyl-disulfonamide (4) were prepared and employed as base catalysts or as ligand for titanium(IV) complexes in the asymmetric addition of diethylzinc to aromatic aldehydes. High enantioselectivity up to almost 100% ee was achieved for the alkylation of benzaldehyde and p-methoxybenzaldehyde with 1 or 3. In contrast, however, the β-aminoalcohol (2a) and phosphinamides (2b and c) that are ubiquitous classes of base catalysts for this reaction proved inefficient in our hands, regardless of the types of substrates or reaction conditions. Comparative studies show that there exist various reaction parameters governing not only chemical yields but also optical yields. These include steric and electronic environment of the substrate, the solvent, the reaction temperature, and the nature of the ferrocene moieties.     

Chiral β-diketonate ligands of ‘pseudo planar chiral’ topology: enantioselective synthesis and transition metal complexation

A practical enantioselective synthesis of chiral β-diketonate ligands 1a-1d, which are of ‘pseudo planar-chiral’ topology, is described. Additionally, the first chiral bis(diketonates) 2a-2c, ligands of C₂-symmetry that are isoelectronic with respect to related salen ligand systems, have been prepared. Protocols for the metallation of ligands 1a-1d, 2b and 2c are reported.     

Novel C1-symmetric chiral crown ethers bearing rosin acids groups: synthesis and enantiomeric recognition for ammonium salts

Four types of novel C₁-symmetric chiral crown ethers including 28-crown-8, 20-crown-6, 17-crown-5 and 14-crown-3 (9a–m) were synthesized and their enantiodiscriminating abilities with protonated primary amines (10–14) were examined by ¹H NMR spectroscopy. 20-crown-6 crown ethers exhibited good chiral recognition properties toward these guests and showed different complementarity to some chiral guests, indicating that 20-crown-6 crown ethers could be used as a chiral NMR solvating agent to determine the enantiopurity of these guests. In addition, the binding model and binding site between the hosts and guests were also studied by the computational modeling and experimental calculation.     

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones are discussed. The use of a series of C2-symmetric chiral crown ethers 2 or 3 derived from commercially available (R)-1,1′-bi-2-naphthol for the enantioselective trifluoromethylation of 2-naphthyl aldehyde 1a with (trifluoromethyl)trimethylsilane in the presence of a base was attempted. Iodo-substituted crown ether 2b was found to be the most effective in the model reaction. Moderate enantioselectivities were observed for the trifluoromethylation of both aryl or alkyl aldehydes and alkyl aryl ketones in 21-44% ees. Although the ees are still improvable, this is the first example of a chiral crown ether-catalyzed enantioselective trifluoromethylation reaction.     

Chiral pyridine imidazolines from C1-symmetric diamines: Synthesis, arene ruthenium complexes and application as asymmetric catalysis for Diels-Alder reactions

Condensation of mono N-substituted chiral ethylenediamines and pyridine-2-methoxyimidate gives new chiral pyridine imidazolines (1a-c). These react with [RuCl₂(mes)]₂ (mes = 1,3,5-trimethyl benzene) in the presence of NaSbF₆ to give complexes [RuCl(L)(mes)][SbF₆] (5a-c) which after treatment with AgSbF₆ are enantioselective catalysts for the Diels-Alder reaction of methacrolein and cyclopentadiene. The imidazoline catalysts are less selective than the corresponding oxazoline ones. Compounds 1a, 5b and 5c have been characterised by X-ray crystallography.     

Highly enantioselective synthesis and potential biological activity of chiral novel nucleoside analogues containing adenine and naturally phenol derivatives

This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(9′-adeninyl)-1,4-butanediol 8. The absolute configuration of 8 was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(9′-adeninyl)-1,4-butanediol 8 and phenoxy components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside analogues 1a-1e. The regioselectivity of the reaction was established by NMR methods, especially through ¹³C NMR shifts and NOE effect observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of cytopathogenicity against different cancer cells and exhibited potential anticancer activity.     

Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors

Novel unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The chiral recognition of N-Boc-protected amino acids by 2a and 2b has been investigated. Sensor 2a possesses higher sensitivity and enantioselectivity than sensor 2b does. Job analysis and nonlinear regression results show that 2a can form a 1:1 stoichiometric complex with a N-Boc-protected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids.     

Stereogenic properties of spiranes combined with one or two equivalent conventional centres of chirality

Derivatives of the tri-spirane pentaerythritoxy-cyclophosphazene compound 1 have been used to investigate the stereogenic properties of spiranes combined with either one or two conventional centres of chirality. In compound 1, the two inner rings are carbocyclic and symmetrical and the two outer rings are cyclotriphosphazenes substituted in different positions to provide the conventional centres of chirality. Reaction of 1 in a 1:1 molar ratio with the unsymmetrical dinucleophilic reagent, 1,3-aminopropanol, gave the mono-spiro substituted derivative 2, which was shown to exist as a racemate by X-ray crystallography and ³¹P NMR spectroscopy on addition of a chiral solvating agent (CSA). Reaction of 1 with 1,3-aminopropanol in a 1:2 molar ratio gave three diastereoisomeric di-mono-spiro products 3a-3c, which were all shown to be racemates using a combination of X-ray crystallography (3a, 3c) and ³¹P NMR spectroscopy on addition of a CSA (3b), thus proving the case of the stereogenic properties of spirane molecules combined with two equivalent conventional centres of chirality. It is also shown by quantitative ³¹P NMR spectroscopy of the reaction mixture and by isolation of reaction products that the proportions of the diastereoisomers 3a:3b:3c are in approximate ratios of 1:2:1, respectively, and these results have been rationalised by analysis of the stereogenic properties of the series of reactions 1 → 2 → 3.     

Synthesis and characterization of a novel chiral azomethine diselenide

The first chiral diselenide 9 having an ortho-azomethine functional group has been synthesized by the reaction of bis(o-formylphenyl) diselenide with the chiral amine R(+)-(1-phenylethylamine). The chiral diselenide 9 was further characterized by derivatizing it into the corresponding selenenyl halides. The derivatives are characterized by single crystal X-ray diffraction studies. In the solid state, the bromide derivative 11 shows the strongest Se?N intramolecular interaction. The chiral azomethine diselenide 9 has been further reduced to afford the diselenide 13. The monoselenide analogues of 9 and 13 have also been synthesized.     

Nucleophilic fluorination of amino alcohols and diols using Deoxofluor

Various fluorinated chiral compounds were synthesized using bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) as a nucleophilic fluorinating reagent. Reactions of Deoxofluor (1) with amino alcohols (2a-d) and diols (2e-g) in methylene chloride at room temperature led to the formation of the corresponding fluoro derivatives (3a-g) in good yields.     

Enantioselective oxidation of sulfides with hydrogen peroxide catalyzed by vanadium complex of sterically hindered chiral Schiff bases

Sterically hindered chiral Schiff base ligands 4a-d were prepared from an aldehyde derived from BINOL. The vanadium complexes of the ligands catalyze an efficient, enantioselective H₂O₂-promoted sulfoxidation of alkyl aryl sulfides, and enantioselectivities as high as 98-99% ee are observed in the sulfoxidation of benzyl aryl sulfides.     

Effect of the rigidity and flexibility features of 2-pyridinyl or 8-quinolinyl based N-N chiral ligands on the stereochemical properties of [Pd(N-N)Cl2] complexes

The [Pd(N-N^∗)Cl₂] complexes have been obtained, as yellow solids, in almost quantitative yields; N-N^∗ indicate bidentate chiral ligands (S_a)-1, (S_a)-2, (S,S)-3, (R,R)-4, containing the rigid 2-pyridinyl or 8-quinolinyl building block skeleton and the C₂-symmetric chiral framework trans-2,5-dimethylpyrrolidinyl or (S)-(+)-2,2′-(2-azapropane-1,3-diyl)-1,1′-binaphthalene. The ligands pairs have the same C₂-symmetric chiral framework but different building block skeleton, beyond that for the basicity in the N-donor atoms, for rigidity and flexibility features. The N-N^∗ ligands act as chelating ligands leading a square planar geometry. The compounds [Pd(S,S-3)Cl₂] and [Pd(R,R-4)Cl₂] have been also characterised by X-ray diffraction. The rigidity and flexibility features of (S,S)-3 and (R,R)-4 ligands induce a different orientation of the trans-2,5-dimethylpyrrolidinyl moiety with respect to the pyridinyl and quinolinyl plane. This work shows that intrinsic rigidity and flexibility are not enough to define the ligand properties and to preview the effects that they induce on the reactivity of the metal complex.     

Synthesis and functional evaluation of chiral dendrimer-triamine-coordinated Gd complexes as highly sensitive MRI contrast agents

Novel chiral dendrimer-triamine-coordinated Gd complexes were synthesized and shown to have longitudinal relaxivity (r1) 3 times higher than that of clinically used Gd-DTPA. The pharmacokinetic differences between optical isomers were estimated from the affinity of 2-(R) and 2-(S) with bovine serum albumin (BSA), respectively, by a quartz crystal microbalance (QCM) measurement. As a result, the association constant K_a of 2-(S) was about 4 times higher than that of 2-(R), which means that 2-(S) is retained in the vascular retention for a longer time after administration. This result was also supported by T1-weighted MR images of mice before and after the intravenous injection of 2-(R) and 2-(S), as well as the time-course of the signal intensities (SI) at the blood vessels and quantification of Gd³⁺ concentration in the blood and urine.     

Aza-Michael addition of chiral hydrazines to alkylidene malonates

The conjugate spontaneous addition of chiral N,N-dialkylhydrazines 1 to dimethyl alkylidene/arylidene malonates 2, 5-10 affords the corresponding β-hydrazino esters in moderate-to-good yields and selectivities. d-Mannitol-derived hydrazine 1a afforded best results, mainly due to the higher stability of the products 3, 11-16.     

Resolution of BIPHEP on Rh with a chiral diene auxiliary

Resolution of the atropisomeric chiral BIPHEP ligand on Rh has been achieved with the aid of 2-(4-tert-butyl-phenyl)-8-methoxy-1,8-dimethyl-bicyclo[2.2.2]octa-2,5-diene, a chiral chelating diene ligand. The diene complex 3 containing an (S)-BIPHEP ligand was found to be configurationally stable in CDCl₃ solution at RT. Conversion of the diene complex 3 to a dicarbonyl Rh complex 4 that had a barrier of 25.0 kcal/mol for atropisomerization of the BIPHEP ligand. Preliminary studies of the use of the resolved complex 3 for catalysis are presented.