Chiral amino-urea derivatives of (1R,2R)-1,2-diaminocyclohexane as ligands in the ruthenium catalysed asymmetric reduction of aromatic ketones by hydride transfer

Several new chiral urea and thiourea ligands have been prepared by reaction of (1R,2R)-1,2-diaminocyclohexane with various organic isocyanates and isothiocyanates. These were used as ligands in the ruthenium catalysed enantioselective reduction of aromatic ketones by isopropanol. The reduction proceeded at room temperature using 2 mol% of ruthenium catalyst to give good yields of the (R)-alcohol with enantiomeric excesses of up to 83%. By contrast, the use of bis-urea ligands gave much lower enantioselectivities. Amino-thiourea ligands led to the (S)-alcohol with low enantiomeric excess.     

New chiral ligands and iron(III) complexes based on 2,6-bis(1-benzyl-4-isopropyl-4-methyl-4,5-dihydro-1H-imidazol-5-on-2-yl)pyridines

New ligands and their complexes with iron(III) chloride have been suggested and prepared: (R,S)-, (R,R)- and (S,S)-2,6-bis(1-benzyl-4-isopropyl-4-methyl-4,5-dihydro-1H-imidazol-5-on-2-yl) pyridines. Both the ligands and their complexes were characterised by ¹H and ¹³C NMR spectroscopy, optical rotation and X-ray diffraction.     

Synthesis and screening of peptoid arrays on cellulose membranes

Rapid synthesis and screening of compound libraries enables the accelerated identification of novel protein ligands in order to support processes like analysis of protein interactions, drug target discovery or lead structure discovery. SPOT synthesis—a well established method for the rapid preparation of peptide arrays—has recently been extended to the field of nonpeptides. In this contribution we report on the systematic evaluation of the SPOT technique for the assembly of N-alkylglycine (peptoid) library arrays. In the course of this investigation bromoacetic acid 2,4-dinitrophenylester (1a) was identified to be the most suited agent for bromoacetylation in terms of yield and N-selectivity enabling straightforward submonomer synthesis on hydroxy-group rich cellulose membranes. The potential of this method for the rapid identification of novel nonpeptidic protein ligands was demonstrated by synthesis and screening of a library consisting of 8000 peptoids and peptomers (i.e. their hybrids with α-substituted amino acids) allowing the identification of micromolar ligands for the monoclonal antibody Tab-2.     

Screening of a library of hemisalen ligands in asymmetric H-transfer: Reduction of aromatic ketones in water

A library of chiral hemisalen ligands (30) was realized. The ligands were synthesized by the condensation of salicylaldehyde derivatives with amino-alcohols (amino-indanol or substituted amino-ethanol) and characterized. These ligands associated with ruthenium (II) precursors were tested on the asymmetric transfer hydrogenation (ATH) of aromatic ketones by sodium formate in water. The different substituent pattern on the ligand (electronic and hindrance effects on different positions) as well as the ruthenium precursor were investigated. The best compromise in terms of conversion and chiral induction led to the complex [RuCl₂(mesitylene)]₂ coordinated to (1S,2R)-1-((E)-(3-(dimethyl(phenyl)silyl)-2-hydroxy-5-methoxy benzylidene) amino)-2,3-dihydro-1H-inden-2-ol (L25). It reduces acetophenone in 95% yield and 91% ee in 18 h at 30 °C.     

Synthesis of novel P-ketimine bidentate ferrocenyl ligands with central and planar chirality and comparsion in the catalytic activity between P-ketimine and P-aldimine

A series of novel ferrocenylphosphine-ketimine ligands 6 were prepared by reaction of (R,S_p)-PPFNH₂-R or (S,S_p)-PPFNH₂ with a variety of m-substituted acetophenones. A different catalytic activity was observed between ferrocenylphosphine-ketimine ligands and corresponding aldimine ligands. The efficiency and diastereomeric impact of these ferrocenylphosphine-ketimine ligands in Pd-catalyzed asymmetric allylic alkylation were first investigated, and higher enantioselectivity of over 98% e.e. with 95% yield was obtained by the use of ferrocenylphosphine-ketimine ligands. However, in Rh-catalyzed asymmetric hydrosilylation of aryl ketones, only 42% e.e. was obtained by the use of ferrocenylphosphine-ketimine ligands compared to 90% e.e. with the use of aldimine ligands.     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

Diamidophosphites with remote P1-stereocentres and their performance in Pd-catalyzed enantioselective reactions

Diamidophosphite ligands based on 1,1′-bis(hydroxymethyl)ferrocene or N¹,N²-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)oxalamide and bearing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms were obtained. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 70% ee in Pd-catalyzed desymmetrizations of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol bis-carbamate and up to 80% ee in Pd-catalyzed allylic alkylations of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate. Results obtained with a diamidophosphite containing an oxalamide framework show the considerable potential of such ligands in enantioselective catalysis.     

Microbial and homogenous asymmetric catalysis in the reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone

Two complementary approaches for the enantioselective reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone 1 are described and compared: microbial versus asymmetric reduction of ketones through asymmetric hydrogen transfer. Among the various microorganisms screened, Lactobacillus kefir and Aspergillus niger reduced ketone 1 to the corresponding (R)-alcohol (R)-2. The (S)-alcohol (S)-2 was obtained by reduction of 1 using homogenous asymmetric catalysis. The configuration of the alcohol in both the biocatalysis and hydrogen transfer approaches was controlled by the choice of the enzyme and by the configuration of ligands, respectively. Both enantiomers were obtained in high yield and ee.     

Multiple Diastereomers of [M n+(α m -P2W17O61)2](20−n)− (M=UIV, ThIV, CeIII; m=1, 2). Syn- and Anti-Conformations of the Polytungstate Ligands in α1α1, α1α2, and α2α2 Complexes

Several examples of the complexes, [M(P₂W₁₇O₆₁)₂] ^n? (M=U^IV, Th^IV, Ce^III), containing both α ₁ (C ₁) and α ₂ (C _s ) isomers of the tungstophosphate ligands, have been synthesized and characterized by X-ray crystallography and ³¹P NMR spectroscopy. In every case the heteroatom M has the anticipated square antiprism coordination. When both ligands are α ₂ (the U^IV and Ce^III complexes) the solid state structure adopts a syn-conformation of the ligands, as had been previously demonstrated for M=Ce^IV and Lu^III; in solution a single set of P-NMR lines is observed, consistent with a single unique structure or rapid interconversion of syn- and anti-forms. When one or both ligands are α ₁ (Uα ₁ α ₁, Uα ₁ α ₂, Thα ₁ α ₁, Ceα ₁ α ₂) multiline P-NMR spectra reveal the presence of two major diastereomers in solution, presumably the syn- and anti-forms. In the solid state, crystals of ammonium or potassium salts of the U and Ce complexes contain anti-conformers, while the Th complex proves to be syn. Variable temperature (～25–～60°C) P-NMR spectroscopy of solutions of the Uα ₁ α ₁ complex reveals the onset of syn-anti interconversion together with the irreversible formation of minor amounts of other diastereomers generated by dissociation and scrambling of the enantiomers of the polytungstate ligands.     

Structural and electronic effects of oxazolidine ligands derived from (1R,2S)-ephedrine in the asymmetric addition of diethylzinc to aldehydes

The purpose of this research was to determine the activity of chiral oxazolidine ligands prepared from (1R,2S)-ephedrine for the enantioselective addition of diethylzinc to aldehydes. The configuration on the newly formed C2 stereogenic center was determined as (2S) by X-ray structural analysis. Oxazolidine ligands reveal medium enantioselectivity with the ee exceeding 57%, and the yields obtained being 68–99%. The results indicate that the absolute configuration of the addition product depends not only on the N3-methyl as an important stereocontrol element but also on both the electronic and steric effects of the substrates and oxazolidine ligands.     

Two chiral mononuclear and one-dimensional cadmium(II) complexes constructed by (1R,2R)-N1,N2-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives: Effect of positional isomerism

Reactions of (1R,2R)-N¹,N²-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives, (1R,2R)-2-bpcd and (1R,2R)-3-bpcd [(1R,2R)-2-bpcd = (1R,2R)-N¹,N²-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine, (1R,2R)-3-bpcd = (1R,2R)-N¹,N²-bis(pyridin-3-ylmethyl)cyclohexane-1,2-diamine], with CdI₂ in an analogous way led to the formation of a chiral discrete mononuclear complex and a chiral one-dimensional polymeric chain, respectively, which may be attributed to the positional isomerism of the ligands. The chiral organic ligands and complexes display luminescent properties indicating that they may have a potential application as optical materials. Powder second-harmonic generation (SHG) efficiency measurement shows that the SHG efficiency of the complexes is approximately 0.3 and 0.45 times that of KDP, respectively.     

Acetyl-BINOL as mimic for chiral β-diketonates: a building block for new modular ligands

α-Acetyl-(S)-BINOL was prepared by ortho-lithiation and subsequent acetylation of acetal-protected (S)-BINOL. The β-hydroxyketone moiety of this compound is herein a structural mimic for a β-diketonate and forms six-membered chelates with transition metal ions. The second hydroxy-function was submitted to esterification with several carboxylic acids bearing another donor function, thus, new tridentate chiral ligands were obtained. Out of this library the l-proline-α-acetyl-(S)-BINOL-ester was identified to be most effective for the titanium-mediated addition of Et₂Zn to PhCHO yielding the respective secondary alcohol with up to 93% ee, which is better than with using (S)-BINOL itself. Besides a solvent dependency (use of MeCN is optimal), the proper choice of the counter-ion is crucial: anion exchange of bromide by trifluoroacetate gave a significant increase of enantioselectivity.     

Diastereomeric P1-chiral diamidophosphites with terpene fragments in asymmetric catalysis

Diamidophosphite P¹-monodentate, ligands based on terpene alcohols and (S)- or (R)-(2-anilinomethyl)pyrrolidine, induce high enantioselectivities (ee’s up to 99%) in Pd-catalyzed allylic substitution reactions. In the Pd-catalyzed deracemization of ethyl (E)-1,3-diphenylallyl carbonate up to 92% enantioselectivity has been achieved. The Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters leads to a maximum of 56% ee with quantitative conversion. Diastereomeric diamidophosphites prepared from [(1S)-endo]-(−)-borneol were found to be the most efficient stereoselectors.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

Synthesis of enantiopure C1 symmetric diphosphines and phosphino-phosphonites with ortho-phenylene backbones

Reaction of 2-(diphenylphosphino)phenylphosphonous acid tetramethyldiamide 1 with (+)-menthol, (1S,2S,3S,5R)-isopinocampheol and (1R,2R)-trans-cyclohexanediol affords enantiopure phosphino-phosphonite ligands 3–5. The X-ray structures of 1 (space group P2₁/n) and 3 (space group P2₁) have been determined. The reaction of 1 with (1R,2R,3S,5R)-(−)-pinanediol proceeds diastereoselectively to afford a novel type of enantiopure phosphino-phosphonite ligand 6 with an asymmetric substituted P atom. On reaction of (+)-cedryl alcohol with 1 the adduct 7 of the phosphonous acid 2-Ph₂PC₆H₄P(O)(H)OH 9 and its dimethylammonium salt is formed through elimination of water and subsequent hydrolysis. The structure of 7 (space group P1̄) was elucidated by X-ray structural analysis. Reduction of the chlorophosphine 8 with LiAlH₄ yields the novel primary–tertiary phosphine 10, which is a valuable starting material for the synthesis of the enantiopure C₁ symmetric bidentate phospholane ligands 11 and 12.     

Design and synthesis of 1,10-phenanthroline based Zn(II) complexes bearing 1D push-pull NLO-phores for tunable quadratic nonlinear optical properties

Three Zn(II) complexes bearing 1,10-phenanthroline and one-dimensional (1D) push-pull NLO-phores with various acceptor strength as well as π-conjugation length have been synthesized in high yields for two-dimensional (2D) nonlinear optical response. The quadratic optical nonlinearity of the ligands and the complexes are measured by the HRS technique. The ligands show small second-order optical nonlinearity (β) comparable to the standard, para-nitroaniline (pNA). However, upon complexation with Zn(II), each complex exhibits large β values showing the importance of metal ion in enhancing the optical nonlinear effect.     

Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified α_vβ₃ and α₅β₁ receptors using biotinylated vitronectin (α_vβ₃) and fibronectin (α₅β₁) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for α_vβ₃ over α₅β₁. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin α_vβ₃). The two RGD ligands showed IC₅₀ values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC₅₀ value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the α_Vβ₃ integrin active site, provided a rationale for the behavior of these ligands toward the receptor.     

Preparation of enantiopure 1,4-amino alcohols derived from [3]ferrocenophanes: use in the asymmetric addition of diethylzinc to benzaldehyde

A series of enantiopure 1,4-amino alcohols with a [3]ferrocenophane backbone have been synthesized. Candida rugosa lipases were used in a key step allowing the resolution of amino alcohol (1S,R_p)-1. Two other amino alcohols (1S,2S,R_p)-2 and (1S,2S,R_p)-3 were prepared starting from (1S,R_p)-1. The new ligands have been used in the asymmetric ethylation of benzaldehyde by diethylzinc and gave good catalytic properties. One of these ligands was particularly efficient, while the yield of the catalytic test reaction was near to 100% and the enantiomeric excess was about 80%. All the ligands directed the catalytic process towards the same (1R)-1-phenylpropanol.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.